Cold menthol receptor-1 antagonists

ABSTRACT

The invention is directed to TRPM8 antagonists of Formula (I). More specifically, the present invention relates to certain novel compounds, methods for preparing compounds, compositions, intermediates and derivatives thereof and methods for treating TRPM8-mediated disorders. Pharmaceutical and veterinary compositions and methods of treating pain and various other disease states or conditions using compounds of the invention are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/799,275, filed May 10, 2006, and to U.S. Provisional PatentApplication No. 60/915,527, filed May 2, 2007, which are herebyincorporated by reference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

BACKGROUND OF THE INVENTION

Transient receptor potential (TRP) channels are non-selective cationchannels that are activated by a variety of stimuli. Numerous members ofthe ion channel family have been identified to date, including thecold-menthol receptor-1, also called TRPM8 (McKerny D D et al. Nature2002; 416(6876): 52-8). Collectively, the TRP channels and relatedTRP-like receptors connote sensory responsivity to the entire continuumof thermal exposure, selectively responding to threshold temperaturesranging from noxious hot through noxious cold as well as to certainchemicals that mimic these sensations. Specifically, TRPM8 is known tobe stimulated by cool to cold temperatures as well as by menthol andicilin, which may be responsible for the therapeutic cooling sensationthat these agents evoke. TRPM8 is located on primary nociceptive neurons(A-delta and C-fibers) and is modulated by inflammation-mediated secondmessenger signals (Abe J et al. Neurosci Lett 2006, 397(1-2):140-4;Premkumar L S et al. J Neurosci 2005; 25(49): 11322-9). The localizationof TRPM8 on both Aδ and C-fibers may provide a basis for abnormal coldsensitivity in pathologic conditions wherein these neurons are altered,resulting in pain, often of a burning nature (Kobayashi K et al. J CompNeurol 2005; 493(4): 596-606; Roza C et al. Pain 2006; 120(1-2): 24-35;Xing H et al. J Neurophysiol 2006; 95(2): 1221-30). Cold intolerance andparadoxical burning sensations induced by chemical or thermal coolingclosely parallel symptoms seen in a wide range of clinical disorders andthus provide a strong rationale for the development of TRPM8 modulatorsas novel antihyperalgesic or antiallodynic agents. TRPM8 is also knownto be expressed in the brain, lung, bladder, gastrointestinal tract,blood vessels, prostate and immune cells, thereby providing thepossibility for therapeutic modulation in a wide range of maladies.

In International Patent Application WO 2006/040136 A1, Lampe, T. et alof Bayer Healthcare AG disclose substituted4-benzyloxy-phenylmethylamide derivatives as cold menthol receptor-1(CMR-1) antagonists for the treatment of urological disorders.

In International Patent Application WO 2006/040103 A1, Alonso-Alija, C.et al of Bayer Healthcare AG disclose methods and pharmaceuticalcompositions for treatment and/or prophylaxis of respiratory diseases ordisorders.

In International Patent Application WO 2007/017092 A1, Lampe, Thomas etal of Bayer Healthcare AG disclose substituted 4-benzyloxy-benzoic acidamide derivatives as cold menthol receptor-1 (CMR-1) antagonists for thetreatment of urological diseases or disorders, chronic pain, neuropathicpain, postoperative pain, rheumatoid arthritic pain, neuralgia,neuropathies, algesia, nerve injury, ischaemia, neurodegeneration,stroke, and inflammatory disorders such as asthma and chronicobstructive pulmonary (or airways) disease (COPD).

In International Patent Application WO 2007/017093 A1, Lampe, Thomas etal of Bayer Healthcare AG disclose substituted 2-benzyloxy-benzoic acidamide derivatives as cold menthol receptor-1 (CMR-1) antagonists for thetreatment of urological diseases or disorders, chronic pain, neuropathicpain, postoperative pain, rheumatoid arthritic pain, neuralgia,neuropathies, algesia, nerve injury, ischaemia, neurodegeneration,stroke, and inflammatory disorders such as asthma and chronicobstructive pulmonary (or airways) disease (COPD).

In International Patent Application WO 2007/017094 A1, Lampe, Thomas etal of Bayer Healthcare AG disclose substitutedbenzyloxy-phenylmethylcarbamate derivatives as cold menthol receptor-1(CMR-1) antagonists for the treatment of urological diseases ordisorders, chronic pain, neuropathic pain, postoperative pain,rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerveinjury, ischaemia, neurodegeneration, stroke, and inflammatory disorderssuch as asthma and chronic obstructive pulmonary (or airways) disease(COPD).

It is an object of the present invention to provide compounds that areTRPM8 antagonists useful for treating TRPM8-mediated disorders. It isanother object of the invention to provide a process for preparingcompounds, compositions, intermediates and derivatives thereof. It is afurther object of the invention to provide methods for treating chronicor acute pain, or the diseases that lead to such pain, and pulmonary orvascular dysfunction. More particularly, the compounds of the presentinvention are useful for the treatment of diseases or conditionsincluding, but not limited to, those that cause inflammatory orneuropathic pain, cold intolerance or cold allodynia, peripheralvascular pain, itch or urinary incontinence, chronic obstructivepulmonary disease, pulmonary hypertension and anxiety or stress-relateddisorders.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula (I)

wherein:

-   A is benzo or pyrido;-   wherein benzo is optionally substituted with a substituent selected    from the group consisting of C₁₋₂alkyl, C₁₋₂alkoxy, hydroxy, fluoro,    chloro, bromo, C₁₋₂alkoxycarbonyl, aminocarbonyl,    (C₁₋₂alkyl)aminocarbonyl, di(C₁₋₂alkyl)aminocarbonyl, and    trifluoromethyl; and benzo is optionally further substituted with a    substituent selected from the group consisting of methyl, methoxy,    hydroxy, fluoro, and chloro;-   and wherein pyrido is optionally substituted with a substituent    selected from the group consisting of fluoro, chloro, bromo, and    methyl; and pyrido is optionally further substituted with fluoro;-   D is d-1 or d-2

-   X is O, S, S(═O), S(O₂), or N—R₆; wherein R₆ is phenyl, C₁₋₄alkyl,    allyl, C₁₋₄alkylsulfonyl, C₁₋₄alkylcarbonyl, or pyridinyl;-   W is C(R₄) or N;-   R₄ is hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy; C₁₋₆alkoxycarbonyl; chloro;    bromo; cyano; trifluoromethyl; phenyl; a heteroaryl selected from    the group consisting of furyl, thienyl, pyrrolyl, oxazolyl,    thiazolyl, pyrazolyl, pyridinyl, and pyrimidinyl; or a    C₃₋₆cycloalkyl;-   wherein phenyl is optionally substituted with an aminocarbonyl,    trifluoromethyl, or trifluoromethoxy substituent; or phenyl is    optionally substituted with one to two substituents independently    selected from the group consisting of C₁₋₂alkyl, C₁₋₂alkoxy, fluoro,    chloro, hydroxy, and cyano;-   and wherein heteroaryl is optionally substituted with bromo or one    to two substituents independently selected from the group consisting    of methyl, fluoro, and chloro;-   R₁ and R₂ are independently selected from the group consisting of    C₁₋₈alkyl; C₁₋₈alkoxy; —O(CH₂)_(p)—O—(CH₂)_(q)CH₃;    —O(CH₂)_(p)—O—(CH₂)_(q)OCH₃; —O(CH₂)_(r)C(O)OCH₃;    —O(CH₂)_(p)OC(O)CH₃; —(CH₂)_(p)—O—(CH₂)_(q)CH₃; phenyl(C₁₋₃)alkyl;    phenyl(C₁₋₃)alkoxy; and C₃₋₈cycloalkyloxy;-   wherein p is an integer from 2 to 6; and wherein q is an integer    from 0 to 4, such that the sum of p and q is less than or equal to    six; wherein r is an integer from 1 to 4;-   and, wherein the phenyl portion of phenyl(C₁₋₃)alkyl and    phenyl(C₁₋₃)alkoxy is optionally substituted with one to two    substituents independently selected from the group consisting of    C₁₋₂alkyl, C₁₋₂alkoxy, trifluoromethyl, hydroxy, cyano, and halogen;-   and further, wherein C₁₋₈alkyl and C₁₋₈alkoxy of R₁ and R₂ are    optionally substituted with hydroxy, difluoromethyl,    trifluoromethyl, C₃₋₆cycloalkyl, carboxy, C₁₋₂alkoxycarbonyl,    di(C₁₋₃alkyl)amino, aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, or    di(C₁₋₃alkyl)aminocarbonyl; provided that when R₁ is    2-(N,N-dimethylamino)-ethoxy, R₂ is other than    2-(N,N-dimethylamino)-ethoxy;-   R₃ is hydrogen, methyl, fluoro, chloro, bromo, or hydroxy; or R₃ is    absent when L is alkene ═CH—;-   L is absent, —(CH₂)_(n)—, —OC₁₋₂alkyl-, or ═CH—; wherein n is 1 or    2;-   B is hydrogen, phenyl, naphthyl, or a heteroaryl selected from the    group consisting of benzothiophenyl, benzo(1,3)dioxalyl, oxazolyl,    thienyl, furanyl, and benzofuranyl;-   wherein the phenyl of B is optionally substituted with hydroxy,    C₁₋₃alkoxy, trifluoromethyl, nitro, amino, phenyl or a heteroaryl    selected from the group consisting of pyridinyl, thienyl, furanyl,    pyrrolyl, oxazolyl, and thiazolyl; and wherein phenyl of B is    optionally further substituted with a substituent selected from the    group consisting of methyl, fluoro, chloro, trifluoromethyl,    methoxy, and hydroxy;-   and wherein the naphthyl of B is optionally substituted with 1 or 2    substituents selected from the group consisting of hydrogen, methyl,    fluoro, chloro, bromo, C₁₋₃alkoxy, hydroxy, and dimethylamino;-   or, the phenyl or heteroaryl substituent of B is optionally    substituted with a substituent independently selected from the group    consisting of C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylthio, fluoro, chloro,    bromo, cyano, hydroxy, trifluoromethyl, trifluoromethylthio,    trifluoromethoxy, difluoromethoxy, trifluoromethanesulfonyl,    C₁₋₂alkoxycarbonyl, aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, and    di(C₁₋₂alkyl)aminocarbonyl;-   and the phenyl or heteroaryl substituent of B is optionally further    substituted with one to two fluoro or chloro substituents;-   provided that when B is hydrogen and L is absent or —(CH₂)_(n)—,    then at least one of R₁ and R₂ is selected from the group consisting    of phenyl(C₁₋₆)alkyl and phenyl(C₁₋₆)alkoxy;    and enantiomers, diastereomers, racemates, and pharmaceutically    acceptable salts thereof;    provided that a compound of Formula (I) is other than-   a compound wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄), R₄ is    methyl, X is S, R₁ and R₂ are each isopropyloxy, R₃ is hydrogen, L    is CH₂, and B is 3,4-difluorophenyl;-   a compound wherein A is 6-trifluoromethyl-benzo, D is d-2, W is    C(R₄), R₄ is methyl, X is S, R₁ and R₂ are each ethoxy, R₃ is    hydrogen, L is CH₂, and B is 3,4-difluorophenyl;-   and further provided that when D is d-2, R₃ is hydrogen, and L is    —(CH₂)_(n)—, then B is optionally substituted with a substituent    other than aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, or    di(C₁₋₂alkyl)aminocarbonyl.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a compound of Formula (I).Also illustrative of the invention is a process for making apharmaceutical composition comprising mixing a compound of Formula (I)and a pharmaceutically acceptable carrier.

The present invention is further directed to methods for treating orameliorating a TRPM8-mediated disorder. In particular, the method of thepresent invention is directed to treating or ameliorating a TRPM8receptor-mediated disorder including, but not limited to, inflammatorypain, cold-intolerance or cold allodynia, peripheral vascular pain, itchor urinary incontinence, chronic obstructive pulmonary disease,pulmonary hypertension and anxiety or stress-related disorders.

The present invention is also directed to methods for producing theinstant compounds and pharmaceutical compositions and medicamentsthereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, with reference to substituents, the term “independently”means that when more than one of such substituent is possible, suchsubstituents may be the same or different from each other.

As used herein, unless otherwise noted, “alkyl” whether used alone or aspart of a substituent group refers to straight and branched carbonchains having 1 to 8 carbon atoms or any number within this range.Therefore, designated numbers of carbon atoms (e.g. C₁₋₈) shall referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. In substituentgroups with multiple alkyl groups such as (C₁₋₆alkyl)₂amino theC₁₋₆alkyl groups of the dialkylamino may be the same or different.

As used herein, unless otherwise noted, the term “alkoxy” refers to anOalkyl substituent group, wherein alkyl is as defined supra. To theextent substituted, an alkyl and alkoxy chain may be substituted on acarbon atom.

As used herein, the terms “alkenyl” and “alkynyl” refer to straight andbranched carbon chains having 2 or more carbon atoms, wherein an alkenylchain has at least one double bond in the chain and an alkynyl chain hasat least one triple bond in the chain.

The term “cycloalkyl” refers to saturated or partially unsaturated,monocyclic or polycyclic hydrocarbon rings of from 3 to 14 carbon atommembers. Examples of such rings include, and are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andadamantyl. Similarly, “cycloalkenyl” refers to a cycloalkyl thatcontains at least one double bond in the ring. Additionally, a“benzo-fused cycloalkyl” is a cycloalkyl ring that is fused to a benzenering. A “heteroaryl-fused cycloalkyl” is a cycloalkyl ring that is fusedto a 5 or 6 membered heteroaryl ring (containing one of O, S or N and,optionally, one additional nitrogen).

The term “heterocyclyl” refers to a nonaromatic cyclic ring of 5 to 7members in which 1 to 2 members are nitrogen, or a nonaromatic cyclicring of 5 to 7 members in which zero, one or two members are nitrogenand up to two members are oxygen or sulfur; wherein, optionally, thering contains zero to one unsaturated bonds, and, optionally, when thering is of 6 or 7 members, it contains up to two unsaturated bonds. Theterm “benzo-fused heterocyclyl” includes a 5 to 7 membered monocyclicheterocyclic ring fused to a benzene ring. The term “heteroaryl-fusedheterocyclyl” refers to 5 to 7 membered monocyclic heterocyclic ringfused to a 5 or 6 membered heteroaryl ring (containing one of O, S or Nand, optionally, one additional nitrogen). The term “cycloalkyl-fusedheterocyclyl” refers to a 5 to 7 membered monocyclic heterocyclic ringfused to a 5 to 7 membered cycloalkyl or cycloalkenyl ring. Furthermore,the term “heterocyclyl-fused heterocycyl” refers to a 5 to 7 memberedmonocyclic heterocyclic ring fused to a 5 to 7 membered heterocyclylring (of the same definition as above but absent the option of a furtherfused ring). For instant compounds of the invention, the carbon atomring members that form the heterocyclyl ring are fully saturated. Othercompounds of the invention may have a partially saturated heterocyclylring. The term “heterocyclyl” also includes a 5 to 7 membered monocyclicheterocycle bridged to form bicyclic rings. Such compounds are notconsidered to be fully aromatic and are not referred to as heteroarylcompounds. Examples of heterocyclyl groups include, and are not limitedto, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl),pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl,pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl andpiperazinyl.

The term “aryl” refers to an unsaturated, aromatic monocyclic ring of 6carbon members or to an unsaturated, aromatic polycyclic ring of from 10to 14 carbon members. Examples of such aryl rings include, and are notlimited to, phenyl, naphthalenyl or anthracenyl. Preferred aryl groupsfor the practice of this invention are phenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic ring of 5 or 6 memberswherein the ring consists of carbon atoms and has at least oneheteroatom member. Suitable heteroatoms include nitrogen, oxygen orsulfur. In the case of 5 membered rings, the heteroaryl ring containsone member of nitrogen, oxygen or sulfur and, in addition, may containup to three additional nitrogens. In the case of 6 membered rings, theheteroaryl ring may contain from one to three nitrogen atoms. For thecase wherein the 6 membered ring has three nitrogens, at most twonitrogen atoms are adjacent.

Optionally, the heteroaryl ring is fused to a benzene ring to form a“benzo fused heteroaryl”; similarly, the heteroaryl ring is optionallyfused to a 5 or 6 membered heteroaryl ring (containing one of O, S or Nand, optionally, one additional nitrogen) to form a “heteroaryl-fusedheteroaryl”; similarly, the heteroaryl ring is optionally fused to a 5to 7 membered cycloalkyl ring or a 5 to 7 membered heterocyclo ring (asdefined supra but absent the option of a further fused ring) to form a“cycloalkyl-fused heteroaryl”. Examples of heteroaryl groups include,and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; examplesof heteroaryl groups with the optionally fused benzene rings includeindolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, indazolyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl,benzothiadiazolyl, benzotriazolyl, quinolizinyl, quinolinyl,isoquinolinyl or quinazolinyl.

The term “arylalkyl” means an alkyl group substituted with an aryl group(e.g., benzyl, phenethyl). Similarly, the term “arylalkoxy” indicates analkoxy group substituted with an aryl group (e.g., benzyloxy).

The term “halogen” refers to fluorine, chlorine, bromine and iodine.Substituents that are substituted with multiple halogens are substitutedin a manner that provides compounds that are stable.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., arylalkyl, alkylamino) the nameis to be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆)refer independently to the number of carbon atoms in an alkyl moiety, anaryl moiety, or in the alkyl portion of a larger substituent in whichalkyl appears as its prefix root. For alkyl and alkoxy substituents, thedesignated number of carbon atoms includes all of the independentmembers included within a given range specified. For example C₁₋₆ alkylwould include methyl, ethyl, propyl, butyl, pentyl and hexylindividually as well as sub-combinations thereof (e.g. C₁₋₂, C₁₋₃, C₁₋₄,C₁₋₅, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅, etc.).

As used herein, when L is “═CH—” in the compounds of Formula (I), Lrepresents an alkene between B and the carbon atom which is bound to aphosphorus atom, taken to form d-1a or d-2a as illustrated below:

In general, under standard nomenclature rules used throughout thisdisclosure, the terminal portion of the designated side chain isdescribed first followed by the adjacent functionality toward the pointof attachment. Thus, for example, a “phenylC₁-C₆ alkylamidoC₁-C₆alkyl”substituent refers to a group of the formula:

Unless otherwise noted, substituents of ring A of the present inventionare named according to the numbering system shown below, in which “X” islabeled position 1.

For example, when A is benzo, then the following numbering systemapplies:

Unless otherwise noted, it is intended that the definition of anysubstituent or variable at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. It isunderstood that substituents and substitution patterns on the compoundsof this invention can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can be readilysynthesized by techniques known in the art as well as those methods setforth herein.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

As used herein, the term “enantiomeric excess” refers to when oneenantiomer is present in greater quantity than the other enantiomer.Such mixtures of two enantiomers, unlike a racemic mixture, will show anet optical rotation. The specific rotation of the mixture may bedetermined with knowledge of the specific rotation of the pureenantiomer, and subsequently the enantiomeric excess (ee) can bedetermined using equation (1)ee=([α]_(obs)/[α]_(max)×100%  (1).

One skilled in the art may determine specific amounts of each enantiomerusing HPLC on a chiral stationary phase. When the amounts of eachenantiomer are known, the enantiomeric excess may be determined usingequation (2):ee=((R−S)/R+S))×100%  (2)wherein R and S are the respective fractions of enantiomers in a mixturesuch that R+S=1.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation or partial alleviation ofthe symptoms of the disease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the therapeuticallyeffective amounts, as well as any product which results, directly orindirectly, from combinations of the specified ingredients in thespecified amounts.

For the purposes of the present invention, the term “antagonist” is usedto refer to a compound capable of producing, depending on thecircumstance, a functional antagonism of the TRPM8 ion channel,including but not limited to competitive antagonists, non-competitiveantagonists, desensitizing agonists, and partial agonists.

For the purposes of the present invention, the terminflammatory/hypersensitivity is used to refer to a condition that ischaracterized by one or more hallmarks of inflammation, including butnot limited to edema, erythema, hyperthermia and pain, and/or by anexaggerated physiologic or pathophysiologic response to one or more thanone type of stimulation, including but not limited to thermal,mechanical and/or chemical stimulation.

An embodiment of the invention is a method of treating or preventingmigraine, post herpetic neuralgia, post traumatic neuralgia, postchemotherapy neuralgia, complex regional pain syndrome I and II (CRPSI/II), fibromyalgia, inflammatory bowel disease, pruritis, asthma,chronic obstructive pulmonary disease, toothache, bone pain or pyresisin a mammal, which method comprises administering to a mammal in need ofsuch treatment or prevention a therapeutically effective amount of aTRPM8 antagonist.

Another embodiment of the invention is a method of treating orpreventing hypertension, peripheral vascular disease, Raynaud's disease,reperfusion injury or frostbite in a mammal, which method comprisesadministering to a mammal in need of such treatment or prevention atherapeutically effective amount of a TRPM8 antagonist.

A further embodiment of the invention is a method of acceleratingpost-anesthetic recovery or post hypothermia recovery in a mammal, whichmethod comprises administering to a mammal in need of such treatment atherapeutically effective amount of a TRPM8 antagonist.

An embodiment of the present invention is directed to compounds ofFormula (I)

wherein:

-   A is benzo or pyrido;    -   wherein benzo is optionally substituted with a substituent        selected from the group consisting of hydrogen, C₁₋₂alkyl,        C₁₋₂alkoxy, hydroxy, fluoro, chloro, bromo, C₁₋₂alkoxycarbonyl,        aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl,        di(C₁₋₂alkyl)aminocarbonyl, and trifluoromethyl; and benzo is        optionally further substituted with a substituent selected from        the group consisting of hydrogen, methyl, methoxy, hydroxy,        fluoro, chloro;-   and wherein pyrido is optionally substituted with a substituent    selected from the group consisting of fluoro, chloro, bromo, and    methyl; and pyrido is optionally further substituted with fluoro;-   D is d-1 or d-2

-   X is O, S, S(═O), S(O₂), or N—R₆; wherein R₆ is phenyl, C₁₋₄alkyl,    allyl, C₁₋₄alkylsulfonyl, C₁₋₄alkylcarbonyl, or pyridinyl;-   W is C(R₄) or N;-   R₄ is hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy; C₁₋₆alkoxycarbonyl; chloro;    bromo; cyano; trifluoromethyl; phenyl; a heteroaryl selected from    the group consisting of furyl, thienyl, pyrrolyl, oxazolyl,    thiazolyl, pyrazolyl, pyridinyl, and pyrimidinyl; or a    C₃₋₆cycloalkyl;-   wherein phenyl is optionally substituted with a trifluoromethyl or    trifluoromethoxy substituent, or phenyl is optionally substituted    with one to two substituents independently selected from the group    consisting of hydrogen, C₁₋₂alkyl, C₁₋₂alkoxy, fluoro, chloro,    hydroxy, and cyano;-   and wherein heteroaryl is optionally substituted with bromo or one    to two substituents independently selected from the group consisting    of methyl, fluoro, and chloro;-   R₁ and R₂ are independently selected from the group consisting of    C₁₋₈alkyl; C₁₋₈alkoxy; —O(CH₂)_(p)—O—(CH₂)_(q)CH₃;    —(CH₂)_(p)—O—(CH₂)_(q)CH₃; phenyl(C₁₋₃)alkyl; phenyl(C₁₋₃)alkoxy;    and C₃₋₈cycloalkyloxy;-   wherein p is an integer from 2 to 6; and wherein q is an integer    from 0 to 4, such that the sum of p and q is less than or equal to    six;-   and, wherein the phenyl portion of phenyl(C₁₋₃)alkyl and    phenyl(C₁₋₃)alkoxy is optionally substituted with one to two    substituents independently selected from the group consisting of    C₁₋₂alkyl, C₁₋₂alkoxy, trifluoromethyl, hydroxy, cyano, and halogen;-   and further, wherein C₁₋₈alkyl and C₁₋₈alkoxy of R₁ and R₂ are    optionally substituted with hydroxy, difluoromethyl,    trifluoromethyl, C₃₋₆cycloalkyl, carboxy, C₁₋₂alkoxycarbonyl,    di(C₁₋₃alkyl)amino, aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, or    di(C₁₋₃alkyl)aminocarbonyl; provided that when R₁ is    2-(N,N-dimethylamino)-ethoxy, R₂ is other than    2-(N,N-dimethylamino)-ethoxy;-   R₃ is hydrogen, methyl, fluoro, chloro, bromo, or hydroxy;-   L is absent, —(CH₂)_(n)—, or —OC₁₋₂alkyl-; wherein n is 1 or 2;-   B is hydrogen, phenyl, naphthyl, or a heteroaryl selected from the    group consisting of benzothiophenyl, benzo(1,3)dioxalyl, oxazolyl,    thienyl, furanyl, and benzofuranyl; wherein the phenyl of B is    optionally substituted with phenyl or a heteroaryl selected from the    group consisting of pyridinyl, thienyl, furanyl, oxazolyl, and    thiazolyl; and wherein phenyl is optionally further substituted with    a substituent selected from the group consisting of methyl, fluoro,    chloro, trifluoromethyl, methoxy, and hydroxy; and-   wherein the naphthyl of B is optionally substituted with 1 or 2    substituents selected from the group consisting of hydrogen, methyl,    fluoro, chloro, bromo, methoxy, hydroxyl, and dimethylamino;-   or, a B substituent other than hydrogen is optionally substituted    with a substituent independently selected from the group consisting    of C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro, bromo, cyano, hydroxy,    trifluoromethyl, trifluoromethylthio, trifluoromethoxy,    methanesulfonyl, trifluoromethanesulfonyl, C₁₋₂alkoxycarbonyl,    aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, and    di(C₁₋₂alkyl)aminocarbonyl; and B is optionally further substituted    with one to two fluoro or chloro substituents;-   provided that when B is hydrogen and L is absent or —(CH₂)_(n)—,    then at least one of R₁ and R₂ is selected from the group consisting    of phenyl(C₁₋₆)alkyl and phenyl(C₁₋₆)alkoxy;-   and enantiomers, diastereomers, racemates, and pharmaceutically    acceptable salts thereof;    provided that a compound of Formula (I) is other than-   a compound wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄), R₄ is    methyl, X is S, R₁ and R₂ are each isopropyloxy, R₃ is hydrogen, L    is CH₂, and B is 3,4-difluorophenyl;    -   or-   a compound wherein A is 6-trifluoromethyl-benzo, D is d-2, W is    C(R₄), R₄ is methyl, X is S, R₁ and R₂ are each ethoxy, R₃ is    hydrogen, L is CH₂, and B is 3,4-difluorophenyl;-   and further provided that when D is d-2, R₃ is hydrogen, and L is    —(CH₂)_(n)—, then B is optionally substituted with a substituent    other than aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, or    di(C₁₋₂alkyl)aminocarbonyl.

Embodiments of the present invention include a compound of Formula (I)wherein:

-   -   a) A is benzo optionally substituted with trifluoromethyl,        C₁₋₂alkyl, or C₁₋₂alkoxy, and optionally further substituted        with a substituent selected from the group consisting of methyl,        methoxy, fluoro, and chloro;    -   b) A is benzo optionally substituted with trifluoromethyl,        C₁₋₂alkyl, C₁₋₂alkoxy, fluoro, or chloro;    -   c) A is benzo optionally substituted with C₁₋₂alkyl, fluoro, or        chloro;    -   d) D is d-2

-   -   e) X is O, S, S(O₂), or N—R₆; wherein R₆ is phenyl;    -   f) X is O, S, or S(O₂);    -   g) X is O or S;    -   h) W is C(R₄);    -   i) R₄ is hydrogen, C₁₋₆alkyl, chloro, bromo, trifluoromethyl,        phenyl, pyridinyl optionally substituted with fluoro, or        C₃₋₆cycloalkyl;    -   j) R₄ is hydrogen, methyl, isopropyl, 2,2-dimethyl-propyl,        chloro, bromo, trifluoromethyl, phenyl, pyridinyl optionally        substituted with fluoro, or C₃₋₆cycloalkyl;    -   k) R₄ is hydrogen, methyl, isopropyl, chloro, bromo,        trifluoromethyl, pyridinyl optionally substituted with fluoro,        cyclopropyl, cyclobutyl, or cyclopentyl;    -   l) R₄ is methyl, isopropyl, chloro, bromo, trifluoromethyl,        pyridinyl optionally substituted with fluoro, cyclopropyl,        cyclobutyl, or cyclopentyl;    -   m) R₁ and R₂ are independently selected from the group        consisting of C₁₋₄alkyl optionally substituted with        di(C₁₋₃alkyl)amino, C₁₋₄alkoxy optionally substituted with        di(C₁₋₃alkyl)amino, —O(CH₂)_(p)—O—(CH₂)_(q)CH₃,        phenyl(C₁₋₃)alkyl, phenyl(C₁₋₃)alkoxy, and C₃₋₆cycloalkyloxy;        wherein p is an integer from 2 to 4 and q is 0;    -   wherein the phenyl portion of phenyl(C₁₋₃)alkyl and        phenyl(C₁₋₃)alkoxy is optionally substituted with one to two        substituents independently selected from the group consisting of        methyl, methoxy, fluoro, chloro, and bromo; provided that when        R₁ is 2-(N,N-dimethylamino)-ethoxy, R₂ is other than        2-(N,N-dimethylamino)-ethoxy;    -   further provided that only one of R₁ and R₂ is phenyl(C₁₋₃)alkyl        or phenyl(C₁₋₃)alkoxy;    -   n) R₁ and R₂ are independently selected from the group        consisting of C₁₋₄alkyl, phenyl(C₁₋₃)alkyl, and C₁₋₄alkoxy;        wherein the phenyl portion of phenyl(C₁₋₃)alkyl is optionally        substituted with methoxy;    -   o) R₁ and R₂ are independently selected from the group        consisting of methyl, isobutyl, ethoxy, and isopropyloxy;    -   p) R₃ is hydrogen, methyl, fluoro, or bromo;    -   q) R₃ is hydrogen or methyl;    -   r) R₃ is hydrogen;    -   s) L is absent, —(CH₂)_(n)—, or —OCH₂—; and n is 1 or 2;    -   t) L is —(CH₂)_(n)— or —OCH₂—; and n is 1;    -   u) L is —(CH₂)_(n)—; and n is 1;    -   v) B is phenyl, naphthyl, or a heteroaryl selected from the        group consisting of benzothiophenyl and benzo(1,3)dioxalyl;    -   wherein the phenyl of B is optionally substituted with phenyl or        pyridinyl; and the phenyl of B is optionally further substituted        with a substituent independently selected from the group        consisting of methyl, fluoro, and chloro;    -   or, B is optionally substituted with a substituent selected from        the group consisting of C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro,        bromo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy,        C₁₋₂alkoxycarbonyl, aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, and        di(C₁₋₂alkyl)aminocarbonyl; and B is optionally further        substituted with a chloro or fluoro substituent;    -   provided that when R₃ is hydrogen, and L is —(CH₂)_(n)— wherein        n is 1 or 2, B is optionally substituted with a substituent        other than aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, or        di(C₁₋₃alkyl)aminocarbonyl;    -   w) B is phenyl, naphthyl, or benzo(1,3)dioxalyl; wherein the        phenyl of B is optionally substituted with phenyl or pyridinyl;    -   or, B is optionally substituted with a substituent selected from        the group consisting of C₁₋₃alkyl, fluoro, chloro, bromo,        trifluoromethyl, and trifluoromethoxy; and B is optionally        further substituted with a chloro or fluoro substituent;    -   x) B is phenyl optionally substituted with phenyl or pyridinyl;        or, B is phenyl optionally substituted with a substituent        independently selected from the group consisting of C₁₋₃alkyl,        fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy;        and B is optionally further substituted with a chloro or fluoro        substituent;    -   y) B is phenyl substituted with a substituent selected from the        group consisting of C₁₋₃alkyl, fluoro, chloro, bromo,        trifluoromethyl, and trifluoromethoxy; and B is optionally        further substituted with a chloro or fluoro substituent; and    -   z) B is phenyl substituted with a substituent selected from the        group consisting of fluoro, chloro, and trifluoromethyl; and B        is optionally further substituted with a chloro or fluoro        substituent;    -   and any combination of embodiments a) through z) above, provided        that it is understood that combinations in which different        embodiments of the same substituent would be combined are        excluded.

Another embodiment of the present invention includes a compound ofFormula (I)

wherein:

-   A is benzo or pyrido;-   wherein benzo is optionally substituted with a substituent selected    from the group consisting of C₁₋₂alkyl, C₁₋₂alkoxy, hydroxy, fluoro,    chloro, bromo, C₁₋₂alkoxycarbonyl, aminocarbonyl,    (C₁₋₂alkyl)aminocarbonyl, di(C₁₋₂alkyl)aminocarbonyl, and    trifluoromethyl; and benzo is optionally further substituted with a    substituent selected from the group consisting of methyl, methoxy,    hydroxy, fluoro, and chloro;-   and wherein pyrido is optionally substituted with a substituent    selected from the group consisting of fluoro, chloro, bromo, and    methyl; and pyrido is optionally further substituted with fluoro;-   D is d-1 or d-2

-   X is O, S, S(═O), S(O₂), or N—R₆; wherein R₆ is phenyl, C₁₋₄alkyl,    allyl, C₁₋₄alkylsulfonyl, C₁₋₄alkylcarbonyl, or pyridinyl; provided    that X is other than N—R₆ when W is N;-   W is C(R₄) or N;-   R₄ is hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy; C₁₋₆alkoxycarbonyl; chloro;    bromo; cyano; trifluoromethyl; phenyl; a heteroaryl selected from    the group consisting of furyl, thienyl, pyrrolyl, oxazolyl,    thiazolyl, pyrazolyl, pyridinyl, and pyrimidinyl; or a    C₃₋₆cycloalkyl;-   wherein phenyl is optionally substituted with an aminocarbonyl,    trifluoromethyl, or trifluoromethoxy substituent; or phenyl is    optionally substituted with one to two substituents independently    selected from the group consisting of C₁₋₂alkyl, C₁₋₂alkoxy, fluoro,    chloro, hydroxy, and cyano;-   and wherein heteroaryl is optionally substituted with bromo or one    to two substituents independently selected from the group consisting    of methyl, fluoro, and chloro;-   R₁ and R₂ are independently selected from the group consisting of    C₁₋₈alkyl; C₁₋₈alkoxy; —O(CH₂)_(p)—O—(CH₂)_(q)CH₃;    —O(CH₂)_(p)—O—(CH₂)_(q)OCH₃; —O(CH₂)_(r)C(O)OCH₃;    —O(CH₂)_(p)OC(O)CH₃; —(CH₂)_(p)—O—(CH₂)_(q)CH₃; phenyl(C₁₋₃)alkyl;    phenyl(C₁₋₃)alkoxy; and C₃₋₈cycloalkyloxy;-   wherein p is an integer from 2 to 6; and wherein q is an integer    from 0 to 4, such that the sum of p and q is less than or equal to    six; wherein r is an integer from 1 to 4;-   and, wherein the phenyl portion of phenyl(C₁₋₃)alkyl and    phenyl(C₁₋₃)alkoxy is optionally substituted with one to two    substituents independently selected from the group consisting of    C₁₋₂alkyl, C₁₋₂alkoxy, trifluoromethyl, hydroxy, cyano, and halogen;-   and further, wherein C₁₋₈alkyl and C₁₋₈alkoxy of R₁ and R₂ are    optionally substituted with hydroxy, difluoromethyl,    trifluoromethyl, C₃₋₆cycloalkyl, carboxy, C₁₋₂alkoxycarbonyl,    di(C₁₋₃alkyl)amino, aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, or    di(C₁₋₃alkyl)aminocarbonyl; provided that when R₁ is    2-(N,N-dimethylamino)ethoxy, R₂ is other than    2-(N,N-dimethylamino)-ethoxy;-   R₃ is hydrogen, methyl, fluoro, chloro, bromo, or hydroxy; or R₃ is    absent when L is alkene ═CH—;-   L is absent, —(CH₂)_(n)—, —OC₁₋₂alkyl-, or ═CH—; wherein n is 1 or    2;-   B is hydrogen, phenyl, naphthyl, or a heteroaryl selected from the    group consisting of benzothiophenyl, benzo(1,3)dioxalyl, oxazolyl,    thienyl, furanyl, and benzofuranyl;-   wherein the phenyl of B is optionally substituted with hydroxy,    C₁₋₃alkoxy, trifluoromethyl, nitro, amino, phenyl or a heteroaryl    selected from the group consisting of pyridinyl, thienyl, furanyl,    pyrrolyl, oxazolyl, and thiazolyl; and wherein phenyl of B is    optionally further substituted with a substituent selected from the    group consisting of methyl, fluoro, chloro, trifluoromethyl,    methoxy, and hydroxy;-   and wherein the naphthyl of B is optionally substituted with 1 or 2    substituents selected from the group consisting of hydrogen, methyl,    fluoro, chloro, bromo, C₁₋₃alkoxy, hydroxy, and dimethylamino;-   or, the phenyl or heteroaryl substituent of B is optionally    substituted with a substituent independently selected from the group    consisting of C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylthio, fluoro, chloro,    bromo, cyano, hydroxy, trifluoromethyl, trifluoromethylthio,    trifluoromethoxy, difluoromethoxy, trifluoromethanesulfonyl,    C₁₋₂alkoxycarbonyl, aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, and    di(C₁₋₂alkyl)aminocarbonyl;-   and the phenyl or heteroaryl substituent of B is optionally further    substituted with one to two fluoro or chloro substituents;-   provided that when B is hydrogen and L is absent or —(CH₂)_(n)—,    then at least one of R₁ and R₂ is selected from the group consisting    of phenyl(C₁₋₆)alkyl and phenyl(C₁₋₆)alkoxy;    and enantiomers, diastereomers, racemates, and pharmaceutically    acceptable salts thereof;    provided that a compound of Formula (I) is other than-   a compound wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄), R₄ is    methyl, X is S, R₁ and R₂ are each isopropyloxy, R₃ is hydrogen, L    is CH₂, and B is 3,4-difluorophenyl;-   a compound wherein A is 6-trifluoromethyl-benzo, D is d-2, W is    C(R₄), R₄ is methyl, X is S, R₁ and R₂ are each ethoxy, R₃ is    hydrogen, L is CH₂, and B is 3,4-difluorophenyl;    and further provided that when D is d-2, R₃ is hydrogen, and L is    —(CH₂)_(n)—, then B is optionally substituted with a substituent    other than aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, or    di(C₁₋₂alkyl)aminocarbonyl.

Further embodiments of the present invention include a compound ofFormula (I) wherein:

-   -   a) A is unsubstituted pyrido or benzo optionally substituted        with trifluoromethyl, C₁₋₂alkyl, fluoro, chloro, bromo, or        C₁₋₂alkoxy, and optionally further substituted with a        substituent selected from the group consisting of methyl,        methoxy, fluoro, and chloro;    -   b) A is benzo optionally substituted with trifluoromethyl,        C₁₋₂alkyl, C₁₋₂alkoxy, fluoro, chloro, or bromo;    -   c) A is benzo optionally substituted with C₁₋₂alkyl, fluoro, or        chloro;    -   d) D is d-2

-   -   e) X is O, S, S(O₂), or N—R₆; wherein R₆ is phenyl; provided        that X is other than N—R₆ when W is N;    -   f) X is O, S, or S(O₂);    -   g) X is O or S;    -   h) W is C(R₄);    -   i) R₄ is hydrogen; C₁₋₆alkyl; chloro; bromo; trifluoromethyl;        phenyl optionally substituted with hydroxy, aminocarbonyl, or        fluoro; pyridinyl optionally substituted with fluoro; thienyl;        or C₃₋₆cycloalkyl;    -   j) R₄ is hydrogen; methyl; isopropyl; 2,2-dimethyl-propyl;        chloro; bromo; trifluoromethyl; phenyl optionally substituted        with hydroxy, aminocarbonyl, or fluoro; pyridinyl optionally        substituted with fluoro; thienyl; or C₃₋₆cycloalkyl;    -   k) R₄ is hydrogen; methyl; isopropyl; chloro; bromo;        trifluoromethyl; phenyl optionally substituted with hydroxy or        fluoro; pyridinyl optionally substituted with fluoro; thienyl;        cyclopropyl; cyclobutyl; or cyclopentyl;    -   l) R₄ is methyl; isopropyl; chloro; bromo; trifluoromethyl;        pyridinyl optionally substituted with fluoro; thienyl;        cyclopropyl; cyclobutyl; or cyclopentyl;    -   m) R₁ and R₂ are independently selected from the group        consisting of C₁₋₄alkyl optionally substituted with        di(C₁₋₃alkyl)amino; C₁₋₅alkoxy optionally substituted with        di(C₁₋₃alkyl)amino; —O(CH₂)_(p)—O—(CH₂)_(q)CH₃;        —O(CH₂)_(r)C(O)OCH₃; —O(CH₂)_(p)OC(O)CH₃; phenyl(C₁₋₃)alkyl;        phenyl(C₁₋₃)alkoxy; and C₃₋₆cycloalkyloxy; wherein p is an        integer from 2 to 4, q is 0, and r is 1; wherein the phenyl        portion of phenyl(C₁₋₃)alkyl and phenyl(C₁₋₃)alkoxy is        optionally substituted with one to two substituents        independently selected from the group consisting of methyl,        methoxy, fluoro, chloro, and bromo; provided that when R₁ is        2-(N,N-dimethylamino)-ethoxy, R₂ is other than        2-(N,N-dimethylamino)-ethoxy;        -   further provided that only one of R₁ and R₂ is            phenyl(C₁₋₃)alkyl or phenyl(C₁₋₃)alkoxy;    -   n) R₁ and R₂ are independently selected from the group        consisting of C₁₋₄alkyl, phenyl(C₁₋₃)alkyl, —OCH₂C(O)OCH₃,        —O(CH₂)₂OC(O)CH₃, and C₁₋₄alkoxy; wherein the phenyl portion of        phenyl(C₁₋₃)alkyl is optionally substituted with methoxy;    -   o) R₁ and R₂ are independently selected from the group        consisting of methyl, isobutyl, ethoxy, and isopropyloxy;    -   p) R₃ is hydrogen, methyl, fluoro, or bromo; or R₃ is absent        when L is ═CH—;    -   q) R₃ is hydrogen or methyl; or R₃ is absent when L is ═CH—;    -   r) R₃ is hydrogen;    -   s) L is absent, —(CH₂)_(n)—, —OCH₂—, or ═CH—; and n is 1 or 2;    -   t) L is —(CH₂)_(n)—, —OCH₂—, or ═CH—; and n is 1;    -   u) L is —(CH₂)_(n)—; and n is 1;    -   v) B is phenyl, naphthyl, or a heteroaryl selected from the        group consisting of benzothiophenyl and benzo(1,3)dioxalyl;        -   wherein the phenyl of B is optionally substituted with            phenyl or pyridinyl; and the phenyl of B is optionally            further substituted with a substituent independently            selected from the group consisting of methyl, fluoro, or            chloro;    -   or, the phenyl or heteroaryl of B is optionally substituted with        a substituent selected from the group consisting of C₁₋₃alkyl,        C₁₋₃alkoxy, fluoro, chloro, bromo, cyano, hydroxy,        trifluoromethyl, trifluoromethoxy, C₁₋₂alkoxycarbonyl,        aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, and        di(C₁₋₂alkyl)aminocarbonyl; and B is optionally further        substituted with a chloro or fluoro substituent;    -   provided that when R₃ is hydrogen, and L is —(CH₂)_(n)— wherein        n is 1 or 2, B is optionally substituted with a substituent        other than aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, or        di(C₁₋₃alkyl)aminocarbonyl;    -   w) B is phenyl, naphthyl, or benzo(1,3)dioxalyl; wherein the        phenyl of B is optionally substituted with phenyl or pyridinyl;    -   or, B other than naphthyl is optionally substituted with a        substituent selected from the group consisting of C₁₋₃alkyl,        fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy;        and B is optionally further substituted with a chloro or fluoro        substituent;    -   x) B is phenyl optionally substituted with phenyl or pyridinyl;    -   or, B is phenyl optionally substituted with a substituent        independently selected from the group consisting of C₁₋₃alkyl,        fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy;        and B is optionally further substituted with a chloro or fluoro        substituent;    -   y) B is phenyl substituted with a substituent selected from the        group consisting of C₁₋₃alkyl, fluoro, chloro, bromo,        trifluoromethyl, and trifluoromethoxy; and B is optionally        further substituted with a chloro or fluoro substituent; and    -   z) B is phenyl substituted with a substituent selected from the        group consisting of fluoro, chloro, and trifluoromethyl; and B        is optionally further substituted with a chloro or fluoro        substituent;

-   and any combination of embodiments a) through z) above, provided    that it is understood that combinations in which different    embodiments of the same substituent would be combined are excluded.

A further embodiment of the present invention is directed to a compoundof Formula (I) wherein:

-   A is unsubstituted pyrido or benzo optionally substituted with    trifluoromethyl, C₁₋₂alkyl, fluoro, chloro, bromo, or C₁₋₂alkoxy,    and optionally further substituted with a substituent selected from    the group consisting of methyl, methoxy, fluoro, and chloro;-   D is d-1 or d-2

-   X is O, S, S(O₂), or N—R₆; wherein R₆ is phenyl; provided that X is    other than N—R₆ when W is N;-   W is C(R₄) or N;-   R₄ is hydrogen; C₁₋₆alkyl; chloro; bromo; trifluoromethyl; phenyl    optionally substituted with hydroxy, aminocarbonyl, or fluoro;    pyridinyl optionally substituted with fluoro; thienyl; or    C₃₋₆cycloalkyl;-   R₁ and R₂ are independently selected from the group consisting of    C₁₋₄alkyl optionally substituted with di(C₁₋₃alkyl)amino; C₁₋₅alkoxy    optionally substituted with di(C₁₋₃alkyl)amino;    —O(CH₂)_(p)—O—(CH₂)_(q)CH₃; —O(CH₂)_(r)C(O)OCH₃;    —O(CH₂)_(p)OC(O)CH₃; phenyl(C₁₋₃)alkyl; phenyl(C₁₋₃)alkoxy; and    C₃₋₆cycloalkyloxy; wherein p is an integer from 2 to 4, q is 0, and    r is 1;-   wherein the phenyl portion of phenyl(C₁₋₃)alkyl and    phenyl(C₁₋₃)alkoxy is optionally substituted with one to two    substituents independently selected from the group consisting of    methyl, methoxy, fluoro, chloro, and bromo;-   provided that when R₁ is 2-(N,N-dimethylamino)-ethoxy, R₂ is other    than 2-(N,N-dimethylamino)-ethoxy;-   further provided that only one of R₁ and R₂ is phenyl(C₁₋₃)alkyl or    phenyl(C₁₋₃)alkoxy;-   R₃ is hydrogen, methyl, fluoro, or bromo; or R₃ is absent when L is    ═CH—;-   L is absent, —(CH₂)_(n)—, —OCH₂—, or ═CH—; and n is 1 or 2;-   B is phenyl, naphthyl, or a heteroaryl selected from the group    consisting of benzothiophenyl and benzo(1,3)dioxalyl;-   wherein the phenyl of B is optionally substituted with phenyl or    pyridinyl; and the phenyl of B is optionally further substituted    with a substituent independently selected from the group consisting    of methyl, fluoro, or chloro;-   or, the phenyl or heteroaryl of B is optionally substituted with a    substituent selected from the group consisting of C₁₋₃alkyl,    C₁₋₃alkoxy, fluoro, chloro, bromo, cyano, hydroxy, trifluoromethyl,    trifluoromethoxy, C₁₋₂alkoxycarbonyl, aminocarbonyl,    (C₁₋₂alkyl)aminocarbonyl, and di(C₁₋₂alkyl)aminocarbonyl; and B is    optionally further substituted with a chloro or fluoro substituent;-   provided that when R₃ is hydrogen, and L is —(CH₂)_(n)— wherein n is    1 or 2, B is optionally substituted with a substituent other than    aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, or    di(C₁₋₃alkyl)aminocarbonyl;-   provided that a compound of Formula (I) is other than-   a compound wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄), R₄ is    methyl, X is S, R₁ and R₂ are each isopropyloxy, R₃ is hydrogen, L    is CH₂, and B is 3,4-difluorophenyl;    or-   a compound wherein A is 6-trifluoromethyl-benzo, D is d-2, W is    C(R₄), R₄ is methyl, X is S, R₁ and R₂ are each ethoxy, R₃ is    hydrogen, L is CH₂, and B is 3,4-difluorophenyl;-   and further provided that when D is d-2, R₃ is hydrogen, and L is    —(CH₂)_(n)—, then B is optionally substituted with a substituent    other than aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, or    di(C₁₋₃alkyl)aminocarbonyl.

A further embodiment of the present invention is directed to a compoundof Formula (I) wherein:

-   A is unsubstituted pyrido or benzo optionally substituted with    trifluoromethyl, C₁₋₂alkyl, fluoro, chloro, bromo, or C₁₋₂alkoxy,    and optionally further substituted with a substituent selected from    the group consisting of methyl, methoxy, fluoro, and chloro;-   D is d-1 or d-2

-   X is O, S, S(O₂), or N—R₆; wherein R₆ is phenyl; provided that X is    other than N—R₆ when W is N;-   W is C(R₄) or N;-   R₄ is hydrogen; C₁₋₆alkyl; chloro; bromo; trifluoromethyl; phenyl    optionally substituted with hydroxy, aminocarbonyl, or fluoro;    pyridinyl optionally substituted with fluoro; thienyl; or    C₃₋₆cycloalkyl;-   R₁ and R₂ are independently selected from the group consisting of    C₁₋₄alkyl optionally substituted with di(C₁₋₃alkyl)amino; C₁₋₅alkoxy    optionally substituted with di(C₁₋₃alkyl)amino;    —O(CH₂)_(p)—O—(CH₂)_(q)CH₃; —O(CH₂)_(r)C(O)OCH₃;    —O(CH₂)_(p)OC(O)CH₃; phenyl(C₁₋₃)alkyl; phenyl(C₁₋₃)alkoxy; and    C₃₋₆cycloalkyloxy; wherein p is an integer from 2 to 4, q is 0, and    r is 1;-   wherein the phenyl portion of phenyl(C₁₋₃)alkyl and    phenyl(C₁₋₃)alkoxy is optionally substituted with one to two    substituents independently selected from the group consisting of    methyl, methoxy, fluoro, chloro, and bromo;-   provided that when R₁ is 2-(N,N-dimethylamino)-ethoxy, R₂ is other    than 2-(N,N-dimethylamino)-ethoxy;-   further provided that only one of R₁ and R₂ is phenyl(C₁₋₃)alkyl or    phenyl(C₁₋₃)alkoxy;-   R₃ is hydrogen, methyl, fluoro, or bromo;-   L is absent, —(CH₂)_(n)—, or —OCH₂—; and n is 1 or 2;-   B is phenyl, naphthyl, or a heteroaryl selected from the group    consisting of benzothiophenyl and benzo(1,3)dioxalyl;-   wherein the phenyl of B is optionally substituted with phenyl or    pyridinyl; and the phenyl of B is optionally further substituted    with a substituent independently selected from the group consisting    of methyl, fluoro, or chloro;-   or, the phenyl or heteroaryl of B is optionally substituted with a    substituent selected from the group consisting of C₁₋₃alkyl,    C₁₋₃alkoxy, fluoro, chloro, bromo, cyano, hydroxy, trifluoromethyl,    trifluoromethoxy, C₁₋₂alkoxycarbonyl, aminocarbonyl,    (C₁₋₂alkyl)aminocarbonyl, and di(C₁₋₂alkyl)aminocarbonyl; and B is    optionally further substituted with a chloro or fluoro substituent;-   provided that when R₃ is hydrogen, and L is —(CH₂)_(n)— wherein n is    1 or 2, B is optionally substituted with a substituent other than    aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, or    di(C₁₋₃alkyl)aminocarbonyl;-   provided that a compound of Formula (I) is other than-   a compound wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄), R₄ is    methyl, X is S, R₁ and R₂ are each isopropyloxy, R₃ is hydrogen, L    is CH₂, and B is 3,4-difluorophenyl;    or-   a compound wherein A is 6-trifluoromethyl-benzo, D is d-2, W is    C(R₄), R₄ is methyl, X is S, R₁ and R₂ are each ethoxy, R₃ is    hydrogen, L is CH₂, and B is 3,4-difluorophenyl;-   and further provided that when D is d-2, R₃ is hydrogen, and L is    —(CH₂)_(n)—, then B is optionally substituted with a substituent    other than aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, or    di(C₁₋₃alkyl)aminocarbonyl.

A further embodiment of the present invention is directed to a compoundof Formula (I) wherein:

-   A is benzo optionally substituted with trifluoromethyl, C₁₋₂alkyl,    C₁₋₂alkoxy, fluoro, chloro, or bromo;-   D is d-1 or d-2

-   X is O, S, or S(O₂);-   W is C(R₄);-   R₄ is hydrogen; methyl; isopropyl; 2,2-dimethyl-propyl; chloro;    bromo; trifluoromethyl; phenyl optionally substituted with hydroxy,    aminocarbonyl, or fluoro; pyridinyl optionally substituted with    fluoro; thienyl; or C₃₋₆cycloalkyl;-   R₁ and R₂ are independently selected from the group consisting of    C₁₋₄alkyl, phenyl(C₁₋₃)alkyl, —OCH₂C(O)OCH₃, —O(CH₂)₂OC(O)CH₃, and    C₁₋₄alkoxy; wherein the phenyl portion of phenyl(C₁₋₃)alkyl is    optionally substituted with methoxy;-   R₃ is hydrogen or methyl; or R₃ is absent when L is ═CH—;-   L is —(CH₂)_(n)—, —OCH₂—, or ═CH—; and n is 1;-   B is phenyl, naphthyl, or benzo(1,3)dioxalyl; wherein the phenyl of    B is optionally substituted with phenyl or pyridinyl;-   or, B other than naphthyl is optionally substituted with a    substituent selected from the group consisting of C₁₋₃alkyl, fluoro,    chloro, bromo, trifluoromethyl, and trifluoromethoxy; and B is    optionally further substituted with a chloro or fluoro substituent;-   and enantiomers, diastereomers, racemates, and pharmaceutically    acceptable salts thereof;-   provided that a compound of Formula (I) is other than-   a compound wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄), R₄ is    methyl, X is S, R₁ and R₂ are each isopropyloxy, R₃ is hydrogen, L    is CH₂, and B is 3,4-difluorophenyl;    or-   a compound wherein A is 6-trifluoromethyl-benzo, D is d-2, W is    C(R₄), R₄ is methyl, X is S, R₁ and R₂ are each ethoxy, R₃ is    hydrogen, L is CH₂, and B is 3,4-difluorophenyl;-   and further provided that when D is d-2, R₃ is hydrogen, and L is    —(CH₂)_(n)—, then B is optionally substituted with a substituent    other than aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, or    di(C₁₋₃alkyl)aminocarbonyl.

Further embodiments of the present invention are directed to a compoundof Formula (I) wherein:

-   A is benzo optionally substituted with C₁₋₂alkyl, fluoro, or chloro;-   D is d-2

-   X is O or S;-   W is C(R₄);-   R₄ is hydrogen; methyl; isopropyl; chloro; bromo; trifluoromethyl;    phenyl optionally substituted with hydroxy or fluoro; pyridinyl    optionally substituted with fluoro; thienyl; cyclopropyl;    cyclobutyl; or cyclopentyl;-   R₁ and R₂ are independently selected from the group consisting of    methyl, isobutyl, ethoxy, and isopropyloxy;-   R₃ is hydrogen;-   L is —(CH₂)_(n)—; and n is 1;-   B is phenyl optionally substituted with phenyl or pyridinyl;-   or, B is phenyl optionally substituted with a substituent    independently selected from the group consisting of C₁₋₃alkyl,    fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; and B    is optionally further substituted with a chloro or fluoro    substituent;-   and enantiomers, diastereomers, racemates, and pharmaceutically    acceptable salts thereof;-   provided that a compound of Formula (I) is other than a compound    wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄), R₄ is methyl, X    is S, R₁ and R₂ are each isopropyloxy, R₃ is hydrogen, L is CH₂, and    B is 3,4-difluorophenyl.

Further embodiments of the present invention are directed to a compoundof Formula (I) wherein:

-   A is benzo optionally substituted with C₁₋₂alkyl, fluoro, or chloro;-   D is d-2

-   X is O or S;-   W is C(R₄);-   R₄ is methyl; isopropyl; chloro; bromo; trifluoromethyl; phenyl    optionally substituted with hydroxy or fluoro; pyridinyl optionally    substituted with fluoro; thienyl; cyclopropyl; cyclobutyl; or    cyclopentyl;-   R₁ and R₂ are independently selected from the group consisting of    methyl, isobutyl, ethoxy, and isopropyloxy;-   R₃ is hydrogen;-   L is —(CH₂)_(n)—; and n is 1;-   B is phenyl substituted with a substituent selected from the group    consisting of C₁₋₃alkyl, fluoro, chloro, bromo, trifluoromethyl, and    trifluoromethoxy; and B is optionally further substituted with a    chloro or fluoro substituent;-   and enantiomers, diastereomers, racemates, and pharmaceutically    acceptable salts thereof;-   provided that a compound of Formula (I) is other than-   a compound wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄), R₄ is    methyl, X is S, R₁ and R₂ are each isopropyloxy, R₃ is hydrogen, L    is CH₂, and B is 3,4-difluorophenyl.

Further embodiments of the present invention are directed to a compoundof Formula (I) wherein:

-   A is benzo optionally substituted with C₁₋₂alkyl, fluoro, or chloro;-   D is d-2

-   X is O or S;-   W is C(R₄);-   R₄ is methyl; isopropyl; chloro; bromo; trifluoromethyl; pyridinyl;    cyclopropyl; cyclobutyl; or cyclopentyl; wherein pyridinyl is    optionally substituted with fluoro;-   R₁ and R₂ are independently selected from the group consisting of    methyl, isobutyl, ethoxy, and isopropyloxy;-   R₃ is hydrogen;-   L is —(CH₂)_(n)—; and n is 1;-   B is phenyl substituted with a substituent selected from the group    consisting of fluoro, chloro, and trifluoromethyl; and B is    optionally further substituted with a chloro or fluoro substituent;-   and enantiomers, diastereomers, racemates, and pharmaceutically    acceptable salts thereof;-   provided that a compound of Formula (I) is other than    -   a compound wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄), R₄        is methyl, X is S, R₁ and R₂ are each isopropyloxy, R₃ is        hydrogen, L is CH₂, and B is 3,4-difluorophenyl.

A further embodiment of the present invention is directed to a compoundFormula (Ia)

selected from the group consisting of

-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    i-propyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopentyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is isobutyl, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 7-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isobutyl, R₂ is isobutyl, R₃ is H, L is OCH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 6-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    i-propyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopropyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is N, X is S, R₁ is    isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-methyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3,5-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopropyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is methyl, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isobutyl, R₂ is isobutyl, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is (2,3-b)pyridin-2-yl, W is    C(R₄), R₄ is methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is isobutyl, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopentyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁, is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and    B is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclobutyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is n-propyl, R₂ is n-propyl, R₃ is H, L is OCH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    trifluoromethyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃    is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is n-propyl, R₂ is n-propyl, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 5-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is naphthalen-2-yl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,5-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is 2,2-dimethyl-propyl, R₂ is    2,2-dimethyl-propyl, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,6-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-methyl-6-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is 5-methyl-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is 4-chloro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-benzo[1,3]dioxol-6-yl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-(pyridin-4-yl)-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,4-dichloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-biphenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is CH₃, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 6-methoxy-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    naphthalen-2-yl;-   a compound of Formula (Ia) wherein A is 4-trifluoromethyl-benzo, W    is C(R₄), R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H,    L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is SO₂, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-methyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    benzothiophen-2-yl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 5-chloro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is bromo,    L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 2,6-dichloro-phenylmethoxy, R₃ is H, L    is absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2,6-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3,5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2,3-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is cyclohexyloxy, R₂ is cyclohexyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is 2-(N,N-dimethylamino)-ethoxy, R₃    is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 2-methyl-phenylmethoxy, R₃ is H, L is    absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 2-chloro-phenylmethoxy, R₃ is H, L is    absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is methyl, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 4-fluoro-phenylmethoxy, R₃ is H, L is    absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 2-fluoro-phenylmethoxy, R₃ is H, L is    absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 2-bromo-phenylmethoxy, R₃ is H, L is    absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is phenylmethoxy, R₃ is H, L is absent, and    B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    5-chloro-benzo[1,3]dioxol-6-yl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,5-di-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), X is S,    R₄ is N,N-dimethylamino-methyl, R₁ is ethoxy, R₂ is ethoxy, R₃ is H,    L is CH₂, and B is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-biphenyl;-   a compound of Formula (Ia) wherein A is 7-trifluoromethyl-benzo, W    is C(R₄), R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H,    L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is 6-chloro-benzo, W is C(R₄),    R₄ is cyclopentyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S(O), R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclohexyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3,5-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 2,3-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is O, R₁ is isobutyl, R₂ is isobutyl, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 2-fluoro-3-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    2-fluoro-pyridin-3-yl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H,    L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    2,2-dimethyl-propyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L    is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    2-fluoro-pyridin-5-yl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H,    L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is (2,3-b)pyridin-2-yl, W is    C(R₄), R₄ is H, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is (2,3-b)pyridin-2-yl, W is    C(R₄), R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3-chloro-phenyl;-   diastereomer A, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is methyl, X is S, R₁ is ethoxy, R₂ is    3-(4-methoxy-phenyl)-propyl, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   diastereomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is methyl, X is S, R₁ is ethoxy, R₂ is    3-(4-methoxy-phenyl)-propyl, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trimethylphenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-methoxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3,5,6-tetrafluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3,5,6-tetrafluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-chloro-5-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-chloro-5-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,5-di-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2,6-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,5-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-3-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-bromo-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 6-bromo-benzyl, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 6-bromo-benzyl, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is methoxy, R₂ is methoxy, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is s-butyl, R₂ is s-butyl, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is s-butyl, R₂ is s-butyl, R₃ is H, L is OCH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is (2,3-b)pyridin-2-yl, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    thien-3-yl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is n-butyloxy, R₂ is n-butyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is 2-(2-methoxy-ethoxy)-ethoxy, R₂ is    2-(2-methoxy-ethoxy)-ethoxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is 3-methyl-butoxy, R₂ is 3-methyl-butoxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is methoxycarbonyl-methoxy, R₂ is    methoxycarbonyl-methoxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is 2-acetoxy-ethoxy, R₂ is 2-acetoxy-ethoxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    2-hydroxy-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    2-fluoro-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    3-fluoro-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    3-aminocarbonyl-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H,    L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    3-methoxycarbonyl-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    4-fluoro-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-hydroxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3,5,6-tetrafluoro-4-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3,5,6-tetrafluoro-4-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-chloro-5-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-chloro-5-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-hydroxy-phenyl;-   enantiomer A, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   enantiomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   enantiomer A, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethoxy-phenyl;-   enantiomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   enantiomer A, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L    is CH₂, and B is 4-fluoro-phenyl;-   enantiomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L    is CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   enantiomer A, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   enantiomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trimethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-methylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-di-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-di-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methoxy-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-chloro-3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-cyano-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-pyrrol-1-yl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-difluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-cyano-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxycarbonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-nitro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-amino-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-dimethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-dihydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-methoxy-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is N(t-butoxycarbonyl), R₁ is isopropyloxy, R₂ is    isopropyloxy, R₃ is H, L is CH₂, and B is    4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is N(methyl), R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is    3-trifluoromethyl-4-fluoro-benzo, W is C(R₄), R₄ is bromo, X is    N(n-propyl), R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is    3-trifluoromethyl-4-fluoro-benzo, W is C(R₄), R₄ is bromo, X is    N(methanesulfonyl), R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H,    L is CH₂, and B is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is N(methylcarbonyl), R₁ is isopropyloxy, R₂ is    isopropyloxy, R₃ is H, L is CH₂, and B is    4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is N(n-propylsulfonyl), R₁ is isopropyloxy, R₂ is    isopropyloxy, R₃ is H, L is CH₂, and B is    4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is absent, L is    ═CH— taken to form an alkene with the phosphorus-bearing adjacent    atom, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is absent,    L is ═CH— taken to form an alkene with the phosphorus-bearing    adjacent atom, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-5-trifluoromethyl-phenyl;    and-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-trifluoromethyl-phenyl.

Further embodiments of the present invention are directed to a compoundof Formula (Ia)

selected from the group consisting of

-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    i-propyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopentyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is isobutyl, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 7-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isobutyl, R₂ is isobutyl, R₃ is H, L is OCH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 6-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    i-propyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopropyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is N, X is S, R₁ is    isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-methyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3,5-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopropyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is methyl, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isobutyl, R₂ is isobutyl, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is (2,3-b)pyridin-2-yl, W is    C(R₄), R₄ is methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is isobutyl, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopentyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclobutyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is n-propyl, R₂ is n-propyl, R₃ is H, L is OCH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    trifluoromethyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃    is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is n-propyl, R₂ is n-propyl, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 5-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is naphthalen-2-yl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,5-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is 2,2-dimethyl-propyl, R₂ is    2,2-dimethyl-propyl, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,6-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-methyl-6-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is 5-methyl-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is 4-chloro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-benzo[1,3]dioxol-6-yl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-(pyridin-4-yl)-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,4-dichloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-biphenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is CH₃, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 6-methoxy-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    naphthalen-2-yl;-   a compound of Formula (Ia) wherein A is 4-trifluoromethyl-benzo, W    is C(R₄), R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H,    L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is SO₂, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-methyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    benzothiophen-2-yl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 5-chloro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is bromo,    L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 2,6-dichloro-phenylmethoxy, R₃ is H, L    is absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2,6-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3,5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2,3-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is cyclohexyloxy, R₂ is cyclohexyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is 2-(N,N-dimethylamino)-ethoxy, R₃    is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 2-methyl-phenylmethoxy, R₃ is H, L is    absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 2-chloro-phenylmethoxy, R₃ is H, L is    absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is methyl, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 4-fluoro-phenylmethoxy, R₃ is H, L is    absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is 2-fluoro-phenylmethoxy, R₃ is H, L is    absent, and B is H;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-methoxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3,5,6-tetrafluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-dimethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-hydroxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-nitro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-pyrrol-1-yl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trimethylphenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is (2,3-b)pyridin-2-yl, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-difluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,5-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3,5,6-tetrafluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-3-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-chloro-5-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is n-butyloxy, R₂ is n-butyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-di-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-chloro-3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-chloro-5-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxycarbonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    2-hydroxy-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-methoxy-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-chloro-5-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-cyano-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylsulfonyl-phenyl;-   enantiomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-cyano-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is s-butyl, R₂ is s-butyl, R₃ is H, L is OCH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is 3-methyl-butoxy, R₂ is 3-methyl-butoxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trimethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    thien-3-yl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is absent,    L is ═CH— taken to form an alkene with the phosphorus-bearing    adjacent atom, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is methoxycarbonyl-methoxy, R₂ is    methoxycarbonyl-methoxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-chloro-5-hydroxy-phenyl;-   enantiomer A, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    2-fluoro-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3,5,6-tetrafluoro-4-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2,6-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is methoxy, R₂ is methoxy, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is    3-trifluoromethyl-4-fluoro-benzo, W is C(R₄), R₄ is bromo, X is    N(methanesulfonyl), R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H,    L is CH₂, and B is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    3-fluoro-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is N(methylcarbonyl), R₁ is isopropyloxy, R₂ is    isopropyloxy, R₃ is H, L is CH₂, and B is    4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3,5,6-tetrafluoro-4-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is absent, L is    ═CH— taken to form an alkene with the phosphorus-bearing adjacent    atom, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is    3-trifluoromethyl-4-fluoro-benzo, W is C(R₄), R₄ is bromo, X is    N(n-propyl), R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is N(methyl), R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is 2-acetoxy-ethoxy, R₂ is 2-acetoxy-ethoxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    4-fluoro-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-amino-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methoxy-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,5-di-trifluoromethyl-phenyl;-   enantiomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L    is CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-di-trifluoromethyl-phenyl;-   enantiomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-5-trifluoromethyl-phenyl;-   enantiomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 4-bromo-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is s-butyl, R₂ is s-butyl, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;    and-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    3-aminocarbonyl-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H,    L is CH₂, and B is 3,4-difluoro-phenyl.

Further embodiments of the present invention are directed to a compoundof Formula (Ia)

selected from the group consisting of

-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    i-propyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopentyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is isobutyl, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 7-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isobutyl, R₂ is isobutyl, R₃ is H, L is OCH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 6-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    i-propyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopropyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is N, X is S, R₁ is    isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-methyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3,5-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopropyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is methyl, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isobutyl, R₂ is isobutyl, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is (2,3-b)pyridin-2-yl, W is    C(R₄), R₄ is methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is isobutyl, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopentyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclobutyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is n-propyl, R₂ is n-propyl, R₃ is H, L is OCH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    trifluoromethyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃    is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is n-propyl, R₂ is n-propyl, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 5-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is naphthalen-2-yl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,5-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is 2,2-dimethyl-propyl, R₂ is    2,2-dimethyl-propyl, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,6-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-methyl-6-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is 5-methyl-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is 4-chloro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂,    and B is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-benzo[1,3]dioxol-6-yl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-(pyridin-4-yl)-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,4-dichloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-biphenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is CH₃, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 6-methoxy-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    naphthalen-2-yl;-   a compound of Formula (Ia) wherein A is 4-trifluoromethyl-benzo, W    is C(R₄), R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H,    L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-methoxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3,5,6-tetrafluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-dimethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-hydroxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-nitro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-pyrrol-1-yl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trimethylphenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is (2,3-b)pyridin-2-yl, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-difluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,5-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3,5,6-tetrafluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-3-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-chloro-5-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is n-butyloxy, R₂ is n-butyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-di-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-chloro-3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-chloro-5-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxycarbonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    2-hydroxy-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-methoxy-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-chloro-5-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-cyano-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylsulfonyl-phenyl;-   enantiomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-cyano-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is s-butyl, R₂ is s-butyl, R₃ is H, L is OCH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is 3-methyl-butoxy, R₂ is 3-methyl-butoxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trimethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    thien-3-yl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is absent,    L is ═CH— taken to form an alkene with the phosphorus-bearing    adjacent atom, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is methoxycarbonyl-methoxy, R₂ is    methoxycarbonyl-methoxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-chloro-5-hydroxy-phenyl;-   enantiomer A, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    2-fluoro-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3,5,6-tetrafluoro-4-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2,6-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is methoxy, R₂ is methoxy, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is    3-trifluoromethyl-4-fluoro-benzo, W is C(R₄), R₄ is bromo, X is    N(methanesulfonyl), R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H,    L is CH₂, and B is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    3-fluoro-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is N(methylcarbonyl), R₁ is isopropyloxy, R₂ is    isopropyloxy, R₃ is H, L is CH₂, and B is    4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3,5,6-tetrafluoro-4-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-trifluoromethyl-phenyl; and-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-5-trifluoromethyl-phenyl.

A further embodiment of the present invention is directed to a compoundof Formula (Ia)

selected from the group consisting of

-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    i-propyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopentyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is isobutyl, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 7-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isobutyl, R₂ is isobutyl, R₃ is H, L is OCH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is 6-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    i-propyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopropyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is N, X is S, R₁ is    isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is CH₂, and B is    3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-methyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-chloro-3,5-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopropyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is methyl, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is isobutyl, R₂ is isobutyl, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is (2,3-b)pyridin-2-yl, W is    C(R₄), R₄ is methyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3-dichloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is isobutyl, R₃ is H, L is CH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclopentyl, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is H,    X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    methyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    cyclobutyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-methoxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3,5,6-tetrafluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-dimethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-hydroxy-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2,3-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-nitro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-pyrrol-1-yl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trimethylphenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is (2,3-b)pyridin-2-yl, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-5-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-difluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is methyl, X is O, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-trifluoromethyl-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-methylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethylthio-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 3,5-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-chloro-4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2,3,5,6-tetrafluoro-4-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-chloro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-3-chloro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-chloro-5-hydroxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-fluoro-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylsulfonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 5-chloro-2-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is n-butyloxy, R₂ is n-butyloxy, R₃ is H, L is    CH₂, and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,5-di-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-bromo-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 4-chloro-3-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 2-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-chloro-5-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-methoxycarbonyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    2-hydroxy-phenyl, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is    CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-methoxy-3-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-4-chloro-5-methoxy-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 3-cyano-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-trifluoromethylsulfonyl-phenyl;-   enantiomer B, a compound of Formula (Ia) wherein A is benzo, W is    C(R₄), R₄ is bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy,    R₃ is H, L is CH₂, and B is 3-trifluoromethyl-4-fluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-cyano-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-4-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is s-butyl, R₂ is s-butyl, R₃ is H, L is OCH₂, and    B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is 3-methyl-butoxy, R₂ is 3-methyl-butoxy, R₃ is    H, L is CH₂, and B is 3,4-difluoro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-trifluoromethyl-4-chloro-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    chloro, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L    is CH₂, and B is 3-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is 4-fluoro-benzo, W is C(R₄),    R₄ is bromo, X is O, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂,    and B is 3,4-difluorophenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 2-fluoro-5-trifluoromethyl-phenyl;-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is isopropyloxy, R₂ is isopropyloxy, R₃ is H, L is    CH₂, and B is 4-trifluoromethyl-phenyl;    and-   a compound of Formula (Ia) wherein A is benzo, W is C(R₄), R₄ is    bromo, X is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 2-fluoro-5-trifluoromethyl-phenyl.

Further embodiments of the present invention are directed to a compoundof Formula (Ib)

selected from the group consisting of:

-   a compound of Formula (Ib) wherein A is benzo, R₄ is H, X is S, R₁    is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    2-fluoro-phenyl;-   a compound of Formula (Ib) wherein A is 5-fluoro-benzo, R₄ is H, X    is S, R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B is    4-fluoro-phenyl; and-   a compound of Formula (Ib) wherein A is 5-chloro-benzo, R₄ is H, X    is N(phenyl), R₁ is ethoxy, R₂ is ethoxy, R₃ is H, L is CH₂, and B    is 4-fluoro-phenyl.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebaic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; andbases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

One embodiment of the present invention is directed to a compositioncomprising the dextrorotatory enantiomer of a compound of formula (I)wherein said composition is substantially free from the levorotatoryisomer of said compound. In the present context, substantially freemeans less than 25%, preferably less than 10%, more preferably less than5%, even more preferably less than 2% and even more preferably less than1% of the levorotatory isomer calculated as.

${\%\mspace{14mu}{levorotatory}} = {\frac{( {{mass}\mspace{14mu}{levorotatory}} )}{( {{mass}\mspace{14mu}{dextrorotatory}} ) + ( {{mass}\mspace{14mu}{levorotatory}} )} \times 100}$

Another embodiment of the present invention is a composition comprisingthe levorotatory enantiomer of a compound of formula (I) wherein saidcomposition is substantially free from the dextrorotatory isomer of saidcompound. In the present context, substantially free from means lessthan 25%, preferably less than 10%, more preferably less than 5%, evenmore preferably less than 2% and even more preferably less than 1% ofthe dextrorotatory isomer calculated as

${\%\mspace{14mu}{dextrorotatory}} = {\frac{( {{mass}\mspace{14mu}{dextrorotatory}} )}{( {{mass}\mspace{14mu}{dextrorotatory}} ) + ( {{mass}\mspace{14mu}{levorotatory}} )} \times 100}$

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Even though the compounds of the present invention (including theirpharmaceutically acceptable salts and pharmaceutically acceptablesolvates) can be administered alone, they will generally be administeredin admixture with a pharmaceutical carrier, excipient or diluentselected with regard to the intended route of administration andstandard pharmaceutical or veterinary practice. Thus, the presentinvention is directed to pharmaceutical and veterinary compositionscomprising compounds of Formula (I) and one or more than onepharmaceutically acceptable carrier, excipient or diluent.

By way of example, in the pharmaceutical and veterinary compositions ofthe present invention, the compounds of the present invention may beadmixed with any suitable binder(s), lubricant(s), suspending agent(s),coating agent(s), and/or solubilising agent(s).

Tablets or capsules of the compounds may be administered singly or twoor more at a time, as appropriate. It is also possible to administer thecompounds in sustained release formulations.

Alternatively, the compounds of the general Formula (I) can beadministered by inhalation (intratracheal or intranasal) or in the formof a suppository or pessary, or they may be applied topically in theform of a lotion, solution, cream, ointment or dusting powder. Analternative means of transdermal administration is by use of a skinpatch. For example, they can be incorporated into a cream consisting ofan aqueous emulsion of polyethylene glycols or liquid paraffin. They canalso be incorporated, at a concentration of between 1 and 10% by weight,into an ointment consisting of a white wax or white soft paraffin basetogether with such stabilizers and preservatives as may be required.

For some applications, preferably the compositions are administeredorally in the form of tablets containing excipients such as starch orlactose, or in capsules or ovules either alone or in admixture withexcipients, or in the form of elixirs, solutions or suspensionscontaining flavoring or coloring agents.

The compositions (as well as the compounds alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly, subcutaneously, intradermally or intrathecally. In thiscase, the compositions will comprise a suitable carrier or diluent.

For parenteral administration, the compositions are best used in theform of a sterile aqueous solution which may contain other substances,for example, enough salts or monosaccharides to make the solutionisotonic with blood.

For buccal or sublingual administration, the compositions may beadministered in the form of tablets or lozenges, which can be formulatedin a conventional manner.

By way of further example, pharmaceutical and veterinary compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral, etc.). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations also may be coated with substances such as sugars orbe entericly-coated so as to modulate the major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater, and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those skilled in that art.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedand will vary with the particular compound used, the mode ofadministration, the strength of the preparation, and the advancement ofthe disease condition. In addition, factors associated with theparticular subject being treated, including subject age, weight, dietand time of administration, will result in the need to adjust the doseto achieve an appropriate therapeutic level. The above dosages are thusexemplary of the average case. There can be, of course, individualinstances wherein higher or lower dosage ranges are merited, and suchare within the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as analgesics is required for a subject in need thereof.

The invention also provides a pharmaceutical or veterinary pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical and veterinary compositions of theinvention. Optionally associated with such container(s) can be a noticein the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration.

As antagonists of the TRPM8 ion channel, the compounds of Formula (I)are useful in methods for treating or preventing a disease or conditionin a mammal in which the disease or condition is affected by themodulation of TRPM8 receptors. Such methods comprise administering to amammal in need of such treatment or prevention a therapeuticallyeffective amount of a compound, salt or solvate of Formula (I). Inparticular, the compounds of Formula (I) are useful for preventing ortreating chronic or acute pain, or diseases causing such pain orconditions, pulmonary or vascular dysfunction. More particularly, thecompounds of Formula (I) are useful for preventing or treatinginflammatory pain, inflammatory hypersensitivity conditions, neuropathicpain, anxiety and depression by administering to a subject in needthereof a therapeutically effective amount of a compound of Formula (I).

Examples of inflammatory pain include pain due to a condition or painstate selected from the group consisting of inflammatory bowel disease,visceral pain, migraine, post herpetic neuralgia, post operative pain,osteoarthritis, rheumatoid arthritis, back pain, lower back pain, jointpain, abdominal pain, chest pain, labor, musculoskeletal diseases, skindiseases, fibromyalgia, toothache, pyresis, burn, sunburn, snake bite,venomous snake bite, spider bite, insect sting, neurogenic/overactivebladder, interstitial cystitis, urinary tract infection, rhinitis,contact dermatitis/hypersensitivity, itch, eczema, pharyngitis,mucositis, enteritis, irritable bowel syndrome, cholecystitis,pancreatitis, postmastectomy pain syndrome, menstrual, endometriosis,sinus headache, tension headache, migraines and arachnoiditis.

One type of inflammatory pain is inflammatory hyperalgesia, which can befurther distinguished as inflammatory somatic hyperalgesia orinflammatory visceral hyperalgesia. Inflammatory somatic hyperalgesiamay be characterized by the presence of an inflammatory hyperalgesicstate in which a hypersensitivity to thermal, mechanical and/or chemicalstimuli exists. Inflammatory visceral hyperalgesia may also becharacterized by the presence of an inflammatory hyperalgesic state,however, with this state an enhanced visceral irritability exists.

Examples of inflammatory hyperalgesia include a condition or pain stateselected from the group consisting of inflammation osteoarthritis,rheumatoid arthritis, back pain, joint pain, abdominal pain,musculoskeletal diseases, skin diseases, post operative pain, headaches,fibromyalgia, toothache, burn, sunburn, insect sting, neurogenicbladder, urinary incontinence, interstitial cystitis, urinary tractinfection, cough, asthma, chronic obstructive pulmonary disease,rhinitis, contact dermatitis/hypersensitivity, itch, eczema,pharyngitis, enteritis, irritable bowel syndrome, inflammatory boweldiseases, such as Crohn's Disease, and ulcerative colitis.

One embodiment of the present invention is directed to a method fortreating inflammatory somatic hyperalgesia in which a hypersensitivityto thermal, mechanical and/or chemical stimuli exists, comprising thestep of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate ofFormula (I).

A further embodiment of the present invention is directed to a methodfor treating inflammatory visceral hyperalgesia in which an enhancedvisceral irritability exists, comprising the step of administering to amammal in need of such treatment a therapeutically effective amount of acompound, salt or solvate of Formula (I).

A further embodiment of the present invention is directed to a methodfor treating neuropathic cold allodynia in which a hypersensitivity to acooling stimuli exists, comprising the step of administering to a mammalin need of such treatment a therapeutically effective amount of acompound, salt or solvate of Formula (I).

Examples of an inflammatory hypersensitivity condition are urinaryincontinence, benign prostatic hypertrophy, cough, asthma, rhinitisand/or nasal hypersensitivity, itch, contact dermatitis and/or dermalallergy, and chronic obstructive pulmonary disease.

Examples of a neuropathic pain include pain due to a condition or painstate selected from the group consisting of cancer, neurologicaldisorders, spine and peripheral nerve surgery, brain tumors, traumaticbrain injury (TBI), spinal cord trauma, chronic pain syndromes, chronicfatigue syndrome, neuralgias (trigeminal neuralgia, glossopharyngealneuralgia, postherpetic neuralgia and causalgia), lupus, sarcoidosis,peripheral neuropathy, bilateral peripheral neuropathy, diabeticneuropathy, central pain, neuropathies associated with spinal cordinjury, stroke, ALS, Parkinson's disease, or multiple sclerosis, sciaticneuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, bony fractures, oral neuropathic pain,Charcot's pain, complex regional pain syndrome I and II (CRPS I/II),radiculopathy, Guillain-barre syndrome, meralgia paresthetica,burning-mouth syndrome, optic neuritis, postfebrile neuritis, migratingneuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder'sneuralgia, splenopalatine neuralgia, supraorbital neuralgia, and vidianneuralgia.

One type of neuropathic pain is neuropathic cold allodynia, which may becharacterized by the presence of a neuropathy-associated allodynic statein which a hypersensitivity to cooling stimuli exists. Examples ofneuropathic cold allodynia include allodynia due to a condition selectedfrom the group consisting of neuropathic pain (neuralgia), pain arisingfrom spine and peripheral nerve surgery or trauma, traumatic braininjury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia,peripheral neuropathy, diabetic neuropathy, central pain, stroke,peripheral neuritis, polyneuritis, complex regional pain syndrome I andII (CRPS I/II) and radiculopathy.

Examples of anxiety are selected from the group consisting of socialanxiety, post traumatic stress disorder, phobias, social phobia, specialphobias, panic disorder, obsessive compulsive disorder, acute stressdisorder, separation anxiety disorder, and generalized anxiety disorder.

Examples of depression are selected from the group consisting of majordepression, bipolar disorder, seasonal affective disorder, post nataldepression, manic depression, and bipolar depression.

One embodiment of the present invention is directed to a method oftreating or preventing migraine, prophylactic migraine, or hypertensionin a mammal, which method comprises administering to a mammal in need ofsuch treatment or prevention a therapeutically effective amount of aTRPM8 antagonist.

A therapeutically effective amount for use of the instant compounds or apharmaceutical composition thereof comprises a dose range from about 0.1mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or,more particularly, from about 10 mg to about 500 mg of active ingredientin a regimen of about 1 to 4 times per day for an average (70 kg) human;although, it is apparent to one skilled in the art that thetherapeutically effective amount for active compounds of the inventionwill vary as will the conditions being treated.

Optimal dosages of the compounds of Formula (I) to be administered forthe treatment of or prevention of TRPM8-mediated disorders may bereadily determined by those skilled in the art, and will vary with theparticular compound used, the mode of administration, the strength ofthe preparation, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing 0.01, 10.0, 50.0, 100, 150,200, 250, and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the subject to be treated.

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated in the schemes that follow. Since the schemes are anillustration, the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The preparation of thevarious starting materials used in the schemes is well within the skillof persons versed in the art.

Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows:

-   [α] specific rotation-   AcOH glacial acetic acid-   AIBN 2,2′-azobisisobutyronitrile-   Bn or Bzl benzyl-   BCTC 4-(3-chloro-pyridin-2-yl)-piperizine-1-carboxylic acid    (4-tert-butyl-phenyl)-amide-   BuLi butyllithium-   Cpd compound-   DAST (diethylamino)sulfur trifluoride-   DCE 1,2-dichloroethane-   DCM dichloromethane-   DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DIEA diisopropylethylamine-   dppf 1,1′-bis(biphenylphosphine)ferrocine-   EDTA ethylenediaminetetraacetic acid-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   h hour-   HEK human embryonic kidney-   HPLC High Performance Liquid Chromatography-   HEPES 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid-   KOtBu potassium t-butoxide-   LAH lithium aluminum hydride-   Me methyl-   MeOH methanol-   min minutes-   Me methyl-   MnO₂ manganese (IV) oxide-   mpk milligrams per kilogram-   MSNT 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole-   NBS N-bromosuccinimide-   NT not tested-   oxone potassium peroxymonosulfate-   Ph Phenyl-   Pd/C palladium on activated carbon-   PdCl₂(dbfp) 1,1′-bis(di-tertbutylphosphino)ferrocene palladium    dichloride-   Pd(OAc)₂ palladium(II) acetate-   Ph₃P triphenylphosphine-   PPA polyphosphoric acid-   rt room temperature-   TEA/Et₃N triethylamine-   THF tetrahydrofuran-   TMS tetramethylsilane-   TMS—Br trimethylsilyl bromide

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the schemes that follow. Since theschemes are an illustration, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

For illustrative purposes only, the intermediates of the followingSchemes are those wherein D of Formula (I) is d-2. Compounds wherein Dof Formula (I) is d-1 may also be prepared by the general methodsdescribed herein with the appropriate starting materials.

Scheme A illustrates the synthesis of compounds of Formula (I) whereinA, D, and W are as defined in Formula (I), and more specifically,wherein W is C(R₄) and 5 R₄ is hydrogen or methyl, and X is O or S.R_(a) of Scheme A is R₁ or R₂, wherein is R₁ and R₂ are each C₁₋₈alkoxy,and L is (CH₂)_(n).

A compound of formula A1 is either commercially available or may beprepared by known methods described in the scientific literature.Substituent G of compounds of formula A1 is a functional group that isreadily converted to a methyl alcohol, such as an aldehyde, ester,anhydride, or carboxylic acid. A compound of formula A1 is converted toa compound of formula A2 using reagents and methods known to one skilledin the art. The alcohol functional group of a compound of formula A2 maybe converted to its corresponding bromide of formula A3 using phosphorustribromide, or the like. A compound of Formula A3 may be reacted with atrialkoxy phosphite to yield a compound of Formula A4. Treatment of acompound of formula A4 with an organometallic base such asn-butyllithium or bis-lithium(trimethylsilyl)amide, followed byalkylation with a compound of formula A5 (wherein B is C₆₋₁₀aryl or aheteroaryl as defined herein) affords a compound of Formula (I)-A.Compounds of formula A5 are either commercially available or may beprepared by known methods described in the scientific literature. The LGgroup of formula A5 is an appropriate leaving group such as chloride,bromide, or the like.

Scheme B illustrates an alternate route for the preparation of certainintermediates of formula A1 wherein R₄ is hydrogen or C₁₋₆alkyl.

An alcohol or thiol of formula B1 (X is O or S) maybe alkylated in thepresence of a base and a compound of formula B2 to yield a compound offormula B3. When X of formula B1 is oxygen, an appropriate base issodium hydride; likewise, when X is sulfur, an appropriate base ispyridine or other tertiary amine. Treatment of a compound of formula B3with PPA (polyphosphoric acid) provides a cyclized compound of formulaB4. The installation of G may be achieved using reagents and methodsknown to one skilled in the art. For example, NBS or bromine in aceticacid may be used to brominate the vinylic carbon atom adjacent to X.Subsequent treatment of the vinyl bromide with n-butyllithium and DMFmay generate a compound of formula A1 wherein G is an aldehyde.Alternatively, the aforementioned bromide may be carboxylated usingcarbon dioxide in the presence of a palladium catalyst in an aproticsolvent to afford a compound of formula A1 wherein G is a carboxylgroup. Similarly, a compound of formula A1 wherein G is an ester may beprepared by the treatment via alkoxy-carbonylation of the vinyl bromidewith carbon dioxide in the presence of a palladium catalyst in analcoholic solvent.

Scheme C illustrates an alternate route for the synthesis ofintermediates of formula C4 wherein W is C(R₄) and R₄ is other thanC₁₋₆alkoxy, C₁₋₆alkoxycarbonyl. In Scheme C, X is O or S and G is anester.

A compound of formula C1 is either commercially available or may beprepared by known methods described in the scientific literature. Acompound of formula C1 may be treated with a base such as sodium hydride(or TEA when R₄ is trifluoromethyl), followed by the addition of anα-hydroxy or α-thiol substituted ester of formula C2 to afford acompound of formula C3. A compound of formula C3 may be further reactedusing the synthetic methods described herein above to form a compound offormula C4.

Scheme D illustrates the synthesis of certain compounds of Formula (I)wherein A and D are as defined herein, and specifically wherein W isC(R₄) and R₄ is bromo, chloro, C₆₋₁₀aryl, or a heteroaryl; X is O or S;R₁ and R₂ are each C₁₋₈alkoxy or C₁₋₈alkyl, and L is (CH₂)_(n).

A compound of Formula (I)-D1 wherein R₄ is hydrogen may be treated withN-bromosuccinimide to give a compound of Formula (I)-D2 wherein R₄ isbromo. Similarly, a compound of Formula (I)-D1 may be converted to acompound of Formula (I)-D2 (wherein R₄ is chloro) by treatment with achlorinating agent such as N-chlorosuccinimide or the like. A compoundof Formula (I)-D2 may be cross-coupled with a boronic acid of formula D1(wherein R₄ is phenyl or a heteroaryl as defined herein) in the presenceof carbonate anion and a palladium catalyst to afford a compound ofFormula (I)-D3. A compound of Formula (I)-D2 wherein R₄ is bromo mayalso be useful as an intermediate for the preparation of compoundswherein R₄ is C₁₋₆alkoxycarbonyl or cyano. A compound of Formula (I)wherein R₄ is C₁₋₆alkoxycarbonyl may be prepared by a palladiumcatalyzed alkoxy-carbonylation in the presence of an alcoholic solventsuch as methanol, ethanol, or the like. Similarly, compound of Formula(I) wherein R₄ is cyano may be prepared by a palladium catalyzedreaction in the presence of zinc (II) cyanide.

Scheme E illustrates the synthesis of compounds of Formula (I) wherein Xis O or S, and R₁ and R₂ are each C₁₋₈alkyl.

A compound of formula E1 is either commercially available or may beprepared by known methods in the scientific literature. A trialkoxyphosphite of formula E2 may be treated with a compound of formula E1 toform a compound of formula E3. A compound of formula E3 may bedeprotonated at the phosphorus atom and alkylated with a compound offormula A3 to form a compound of Formula E4. A compound of formula E4may be treated with an organometallic base such as n-butyllithium andalkylated with a compound of formula A5 to afford a compound of Formula(I)-E.

Scheme F illustrates the synthesis of compounds of Formula (I) wherein Xis O or S, and R₁ and R_(b) are each C₁₋₈alkyl.

A compound of formula F1 (wherein R_(b) is C₁₋₈alkyl) may be treatedwith a compound of formula F2 in the presence of aqueous carbonate anionto form a compound of formula F3. A compound of formula F3 may bedeprotonated with a strong base and treated with a compound of formulaA3 to form a compound of formula F4. A compound of formula F4 may bedeprotonated and subsequently alkylated with a compound of formula A3 asdescribed herein to yield a compound of Formula (I)-F.

Scheme G illustrates the synthesis of compounds of Formula (I) wherein Xis O or S, and R₁ is C₁₋₈alkoxy and R₂ is C₁₋₈alkoxy or C₁₋₈alkyl. Morespecifically, Scheme G describes the preparation of compounds in whichR₁ is a C₁₋₈alkoxy substituted with an appropriate substituent asdefined in Formula (I).

A compound of Formula (I)-G may be treated with sodium azide to form acompound of formula G1. The hydroxy substituent of formula G1 may becoupled with a R_(1b)-substituted alcohol of formula G2 in the presenceof a standard coupling agent, such as MSNT, to afford a compound ofFormula (I)-G1.

Scheme H illustrates the synthesis of compounds of Formula (I) whereinR₃ is methyl, and D is d-1 or d-2.

A compound of formula A4 may be treated with a base, such asn-butyllithium, followed by addition of a methylating agent such asmethyl iodide to install a methyl group of R₃. Subsequent treatment witha second equivalent of n-butyllithium followed by alkylation with acompound of formula A5 affords a compound of Formula (I)-H.

Scheme I illustrates the synthesis of compounds of Formula (I) wherein Xis S(═O) or S(O₂) and D is d-1 or d-2.

A compound of Formula (I)-I1 wherein X is sulfur may be treated with anoxidizing agent such as oxone, hydrogen peroxide, sodium hypochlorite,or the like, to afford a mixture of compounds of Formula (I)-I2 andFormula (I)-I3. Isolated compounds may be obtained from the mixtureusing separation techniques known to one of skill in the art.

Scheme J illustrates the synthesis of compounds of Formula (I) wherein Lis absent, R₃ is hydrogen, and D is d-1 or d-2.

A compound of formula A1 wherein G is an aldehyde may be treated with aB-substituted Grignard reagent of formula J1 to form the alcohol offormula J2. Treatment of the alcohol with a brominating agent such asphosphorus tribromide or the like affords a compound of formula J3,which may be phosphorylated according to the methods described herein toform a compound of Formula (I)-J.

Scheme K illustrates the preparation of compounds of Formula (I) whereinR₃ is fluoro, R₁ and R₂ are C₁₋₆alkoxy, and D is d-1 or d-2.

A compound of formula A1 wherein G is an aldehyde may be treated with aphosphorylating agent of formula K1 to form an alcohol of formula K2.The alcohol of formula K2 may be oxidized with an appropriate oxidizingagent, such as manganese (IV) oxide or DDQ, to form the correspondingcarbonyl compound of formula K3. Treatment of a compound of formula K3with DAST ((diethylamino)sulfur trifluoride) affords the fluorinatedcompound of formula K4. Treatment of a compound of formula K4 with anorganometallic base such as n-butyllithium, followed by alkylation witha compound of formula A5 provides a compound of formula (I)-K.

Scheme L describes the preparation of compounds of the present inventionwherein R₁ and R₂ are C₁₋₆alkoxy, R₃ is hydroxy, and D is d-1 or d-2.

A compound of formula K2 may be O-protected using conventional reagentsand methods (wherein P is a hydroxy protecting group) to afford acompound of formula L1. Treatment of a compound of formula L1 with anorganometallic base followed by alkylation with a compound of formula A5provides a compound of formula L2. Removal of hydroxy-protecting group Pmay be achieved using conventional methods to afford a compound ofFormula (I)-L.

Scheme M describes the preparation of certain compounds of Formula (I)wherein W is C(R₄) and R₄ is C₁₋₆alkoxy, X is O, S, or N—R₆, and ring Ais benzo. D is d-1 or d-2.

A compound of formula M1 may be cyclized with a compound of formula M2to form a fused ring system of formula M3. The hydroxy substituent of M3may be alkylated with a standard alkylating agent (wherein LG is definedherein) to form an R₄-alkoxy substituent of formula M4. Reduction of theester group of a compound of formula M4 using a borane complex, lithiumaluminum hydride, or the like, provides a primary alcohol of formula M5which may be converted to its corresponding bromide using reagents andmethods taught herein. The bromide may then be phosphorylated and thenalkylated with a compound of formula A5 to form a compound of Formula(I)-M.

Scheme N describes the preparation of certain intermediates to preparecompounds of Formula (I) wherein W is C(R₄) and R₄ is C₁₋₆alkoxy, X isO, S, or N—R₆, and ring A is pyrido. D is d-1 or d-2.

A compound of formula N1 may be cyclized with a compound of formula N2(wherein X is S, O, or N—R₆) to form a fused ring system of formula N3.A compound of formula N3 may be further elaborated to a compound ofFormula (I) using the synthetic sequence described for compounds offormula M3.

Scheme P describes the preparation of certain compounds of Formula (I)wherein R₄ is bromo or chloro, X is N—H (wherein R₆ is H), and ring A isbenzo. D is d-1 or d-2.

A compound of formula P1 may be treated with DMSO, potassium t-butoxide,and acetone to form a 2-methyl substituted indole of formula P2. Theindole nitrogen may be protected using a standard nitrogen protectinggroup (PG) to give a compound of formula P3. The 3-position of theindole may be chlorinated or brominated using N-chlorosuccinimide orN-bromosuccinimide, respectively, to give a compound of formula P4(wherein R₄ is chloro or bromo). The methyl group of a compound offormula P4 may be converted to its methyl bromide using a brominatingagent such as N-bromosuccinimide to afford a compound of formula P5 thatis readily phosphorylated, according to the methods described herein, togive a compound of formula P6. Alkylation with a compound of formula A5yields a compound of formula P7, which, upon removal of the nitrogenprotecting group PG, affords a compound of Formula (I)-P. The indoleamino group (wherein X═NH) may be substituted with other R₆ substituentsof the present invention using conventional synthetic methods andreagents to provide compounds of Formula (I)-P1. For example, an alkylhalide, allyl bromide, acid chloride, or sulfonyl chloride may be usedfor the installation of the respective R₆ groups. Arylation of theindole amine may be achieved by nucleophilic aromatic displacement toafford compounds wherein R₆ is phenyl. Treatment of the indole aminewith a strong base such as sodium hydride, followed by the addition of afluoro-substituted pyridinyl will afford a compound of Formula (I)wherein R₆ is pyridinyl.

Scheme Q describes the preparation of certain compounds of Formula (I)wherein W is C(R₄), X is O, S, or N—R₆, and ring A is benzo substitutedwith aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, ordi(C₁₋₂alkyl)aminocarbonyl. In Scheme Q, D is d-1 or d-2, and R₃₀ andR₃₁ are hydrogen or C₁₋₂alkyl.

A compound of formula Q1 may be cyclized with a compound of formula C2to form a fused ring system of formula Q2. Using chemistry describedherein in Scheme B, a compound of formula Q2 can be converted to acompound of formula Q3. Reduction of substituent G of a compound offormula Q3 using a hydride source, borane complex, lithium aluminumhydride, or the like, provides a primary alcohol of formula Q4. Acompound of formula Q4 may be converted to its corresponding bromideusing reagents and methods taught herein. The bromide may then bephosphorylated and subsequently alkylated with a compound of formula A5to form a compound of formula Q5. Carbonylation of a compound of formulaQ5 to afford a compound of formula Q6 may be achieved using a palladiumsource, such as dichlorobis(triphenylphosphine)palladium (II), carbonmonoxide, and a suitable alcoholic solvent, such as ethanol or methanol.Subsequent hydrolysis of the ester of a compound of formula Q6 may beachieved using known methods in the scientific literature to afford acompound of formula Q7, which can be coupled with an amine of formulaHNR₃₀R₃₁ using known methods in the scientific literature to afford acompound of Formula (I)-Q.

Scheme R describes the preparation of certain compounds of Formula (I)wherein W is C(R₄) and R₄ is a C₁₋₆alkoxycarbonyl substituent, X is O,S, or N—R₆, and ring A is benzo or pyrido. D is d-1 or d-2.

Carbonylation of a compound of Formula (I)-D2 to afford a compound offormula Formula (I)-R may be achieved using a palladium source, such asdichlorobis(triphenylphosphine)palladium (II), carbon monoxide, and asuitable alcoholic solvent (C₁₋₆alkyl-OH).

Scheme S describes the preparation of certain compounds of Formula (I)-Swherein W is C(R₄), wherein R₄ is cyano, X is O, S, or N—R₆, and ring Ais a benzo or pyrido. D is d-1 or d-2.

Cyanation of a compound of Formula (I)-D2 to afford a compound offormula Formula (I)-S may be achieved using a cyanide source, such aszinc cyanide, copper (I) cyanide, or sodium cyanide, and an appropriatesolvent, such as dimethylformamide, N-methylpyrrolidine, ordimethylacetamide (DMA).

A 2-methyl substituted compound of formula T1 may be treated withbromine and sodium acetate in acetic acid to form a compound of formulaT2 wherein R₄ is bromo. The 2-methyl substituent of a compound offormula T2 may be converted to its corresponding 2-methyl bromide T3using N-bromosuccinimide. Compounds of formula T3 may be converted tocertain compounds of Formula (I) using analogous chemistry to thatdescribed for compounds of formula A3 to compounds of Formula (I).

Alternatively, a compound of formula T3 may be phosphonylated to thecorresponding compound of formula T4 according to the conditionsdescribed in Scheme A for the conversion of a compound of formula A3 toa compound of formula A4. Subsequently, a compound of formula T4 may betaken to form compounds of Formula (I) using potassium t-butoxide inTHF/diethyl ether at about 55° C. in place of the reaction conditionsdescribed in Scheme A for the conversion of a compound of formula A4 toa compound of formula Formula (I)-A.

To a solution of compound U1 under basic conditions is added an aldehydeof formula U2. Upon heating, a compound of formula U3 is formed, and theresulting alkenyl functionality may be brominated using bromine underacidic conditions to form a dibromide of formula U4. Upon addition of abase such as a tertiary amine, a mixture of alkenes of formulae U5 andU6 may be prepared. The alkene may then be coupled with a boronic acidof formula U7 in the presence of a transition metal catalyst, underbasic conditions, to form a compound of Formula (I)-U

Compounds of Formula (I) may be prepared enantioselectively by reactionof a compound of formula V1 with a compound of formula A5 in thepresence of the chiral catalyst(R,R)-2,6-bis(3,4,5-trifluorophenyl)-3,3′,5,5′-tetrahydro-4,4′-spirobi[dinaphtho[2,1-c:1′,2′-e]azepin]-4-iumbromide or(S,S)-2,6-bis(3,4,5-trifluorophenyl)-3,3′,5,5′-tetrahydro-4,4′-spirobi[dinaphtho[2,1-c:1′,2′-e]azepin]-4-iumbromide, under basic conditions to form the appropriate chiral productof formula (I)-V.

SPECIFIC EXAMPLES Example 1

A. 3-Methyl-benzo[b]thiophene-2-carboxyaldehyde. To a solution of3-methyl-benzo[b]thiophene (Compound 1a) (4.87 g; 30.1 mmol) inanhydrous THF (50 mL), cooled to −69° C., was added a solution of 2.5 Mn-butyllithium in hexanes (14.4 mL; 36.0 mmol), dropwise. The reactionwas allowed to stir at −69° C. for 1 h, to which was then addedanhydrous DMF (5.0 mL; 64.5 mmol), dropwise. The reaction was allowed towarm to ambient temperature, and was then refluxed for 1 h. At thattime, the reaction was cooled, diluted with EtOAc, washed sequentiallywith H₂O and brine, and dried over Na₂SO₄. The mixture was filtered andthe solvent evaporated under reduced pressure to afford Compound 1b.¹H-NMR (300 MHz, DMSO-d₆): δ 10.34 (s, 1H), 7.85-7.90 (m, 2H), 7.42-7.53(m, 2H), 2.79 (s, 3H).

B. (3-Methyl-benzo[b]thiophene-2-yl)-methanol. To a stirred solution ofCompound 1b (2.3 g; 13.0 mmol) in MeOH (30 mL) was added sodiumborohydride (1.0 g; 26.4 mol), in three equal portions, at ambienttemperature. The reaction mixture was stirred for 18 h at roomtemperature, and then the solvent was evaporated in vacuo. The resultantresidue was partitioned between EtOAc and H₂O, and the layers wereseparated. The organic phase was washed sequentially with H₂O and brine,and dried over Na₂SO₄. The mixture was filtered and the solvent removedunder reduced pressure to afford Compound 1c. ¹H-NMR (300 MHz, DMSO-d₆):δ 8.08-8.10 (d, 1H), 7.89-7.91 (d, 1H), 7.49-7.59 (m, 2H), 5.72-5.75 (t,1H), 4.92-4.94 (d, 2H), 2.53 (s, 3H).

C. 2-Bromomethyl-3-methyl-benzo[b]thiophene. To Compound 1c (2.19 g,12.3 mmol) dissolved in anhydrous ether (40 mL) was added phosphoroustribromide (0.583 mL; 18.4 mmol) dropwise at ambient temperature. Thereaction was stirred at ambient temperature for 1 h, diluted with EtOAc,washed sequentially with saturated NaHCO₃, H₂O, and brine, and thendried over Na₂SO₄. The mixture was filtered and the filtrate wasevaporated under reduced pressure to afford Compound 1d. (Note: materialis unstable and is used immediately in next step.)

D. (3-Methyl-benzo[b]thiophen-2-ylmethyl)-phosphonic acid diethyl ester.To a solution of Compound 1d (2.76 g; 11.5 mmol) in toluene (15 mL) wasadded triethyl phosphite, Compound 1e (2.2 mL; 12.6 mmol), and thereaction was refluxed for 18 h. The reaction mixture was cooled,concentrated under reduced pressure and the resultant residue waspurified by flash column chromatography (SiO₂), eluting with ahexanes-EtOAc gradient to afford of Compound 1f. ¹H-NMR (300 MHz,CDCl₃): δ 7.75-7.77 (d, 1H), 7.62-7.64 (d, 1H), 7.27-7.37 (m, 2H),4.04-4.14 (q, 4H), 3.38-3.44 (d, 2H), 2.36-2.37 (d, 3H), 1.25-1.36 (t,6H); LC/MS: C₁₄H₁₉O₃PS: m/z 299.0 (M+1).

E. Cpd 50:[2-(4-Fluoro-phenyl)-1-(3-methyl-benzo[b]thiophene-2-yl)-ethyl]-phosphonicacid diethyl ester. To a solution of Compound 1f (0.2 g; 0.671 mmol) inTHF (3.0 mL) cooled to −70° C., was added a 2.5 M solution ofn-butyllithium in hexanes (0.332 mL; 0.805 mmol), dropwise. The reactionmixture was allowed to stir at −70° C. for 30 min, to which was thenadded a solution of Compound 1g (0.092 mL; 0.739 mmol) in THF (0.7 mL),dropwise. The reaction mixture was allowed to slowly warm to ambienttemperature, and stirred for an additional 30 min before quenching witha solution of saturated aqueous NH₄Cl (1.0 mL). The mixture was dilutedwith EtOAc, washed with H₂O, then brine, and dried over Na₂SO₄. Themixture was then filtered, and the filtrate was concentrated underreduced pressure. The resulting residue was purified by reverse-phasesemi-prep HPLC eluting with a 55% to 75% MeCN—H₂O gradient to affordCompound 50. ¹H-NMR (300 MHz, CDCl₃): δ 7.77-7.79 (m, 1H), 7.53-7.55 (m,1H), 7.28-7.35 (m, 2H), 6.96-7.01 (m, 2H), 6.78-6.84 (m, 2H), 4.10-4.19(m, 3H), 3.91-4.09 (m, 1H), 3.77-3.86 (m, 1H), 3.46-3.53 (m, 1H),3.08-3.16 (m, 1H), 2.00-2.01 (d, 3H), 1.29-1.33 (t, 3H), 1.22-1.25 (t,3H); LC/MS: C₂₁H₂₄FO₃PS: m/z 406.8 (M+1).

Following the procedure described above for Example 1 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 1 452.9 452.1 4 452.9 422.1 7 406.8 406.1 9409.8 408.1 10 424.8 424.1 11 437.1 436.2 14 424.8 424.1 17 424.8 424.118 402.9 402.1 21 458.7 456.0 22 406.8 406.1 23 440.7 440.1 25 440.1439.1 26 402.9 402.1 27 440.7 440.1 28 458.7 458.1 31 474.8 474.1 32418.8 418.1 35 458.7 456.0 37 474.8 474.1 39 442.8 442.1 40 468.7 466.046 438.9 438.1 47 458.7 456.0 48 422.9 422.1 49 490.8 490.1 50 406.8406.1 51 392.9 392.1 52 456.7 456.1 53 508.8 508.2 54 456.7 456.0 55472.8 472.1 56 474.8 474.1 57 472.8 472.1 58 461.1 460.1 59 456.7 456.160 454.8 454.1 61 472.8 472.1 62 467.2 466.2 63 438.9 438.1 66 468.7466.0 67 474.8 474.1 68 442.8 442.1 69 470.9 470.1 70 453.8 452.0 71466.8 466.1 73 508.8 508.1 74 374.9 374.1 75 411.0 410.1 76 474.8 474.078 442.6 442.0 80 393.9 392.1 81 490.8 490.1 83 424.8 424.1 85 410.9408.1 87 377.0 376.1 89 388.8 388.1 90 430.8 430.1 91 456.7 456.1 92487.0 486.1 95 444.7 442.0 96 510.8 510.1 98 426.7 426.1 99 490.8 490.1100 444.7 442.0 101 532.8 532.2 102 442.8 442.1 112 452.7 452.1 113524.7 524.1 115 464.9 464.2 120 423.1 422.1 121 439.0 438.1 122 439.0438.1 125 489.1 488.1 126 523.0 522.1 133 421.2 420.1 134 437.1 436.1202 455.1 454.42 265 394.35 395.1

Cpd 9:[2-(3,4-Difluoro-phenyl)-1-(3-methyl-benzofuran-2-yl)-ethyl]-phosphonicacid diethyl ester. Compound 9 was prepared according to the method ofExample 1, substituting 3-methyl-benzofuran for Compound 1a of Step A.¹H-NMR (300 MHz, DMSO-d₆): δ 7.43-7.48 (m, 2H), 7.14-7.32 (m, 4H),6.96-6.99 (m, 1H), 3.92-4.10 (m, 5H), 3.26-3.30 (t, 2H), 2.02-2.03 (d,3H), 1.21-1.24 (t, 3H), 1.12-1.15 (t, 3H); LC/MS: C₂₁H₂₃F₂O₄P: m/z 409.8(M+1).

Cpd 14:[2-(3,4-Difluoro-phenyl)-1-(3-methyl-benzo[b]thiophen-2-yl)ethyl]-phosphonicacid diethyl ester. Compound 14 was prepared according to the method ofExample 1, substituting 3,4-difluorobenzyl bromide for Compound 1g inStep E. ¹H-NMR (300 MHz, CDCl₃): δ 7.76-7.78 (m, 1H), 7.54-7.56 (m, 1H),7.28-7.35 (m, 2H), 6.86-6.93 (m, 2H), 6.73-6.76 (m, 1H), 4.03-4.18 (m,3H), 3.89-4.01 (m, 1H), 3.74-3.88 (m, 1H), 3.45-3.51 (m, 1H), 3.08-3.16(m, 1H), 2.07 (s, 3H), 1.30-1.33 (t, 3H), 1.18-1.22 (t, 3H); LC/MS:C₂₁H₂₃F₂O₃PS: m/z 424.8 (M+).

Cpd 25: [1-Benzothiazol-2-yl-2-(3,4-difluoro-phenyl)-ethyl]-phosphonicacid diisopropyl ester. Compound 25 was prepared according to the methodof Example 1, substituting benzothiazole-2-carbaldehyde for Compound 1bof Step B, and substituting 3,4-difluorobenzyl bromide for Compound 1gin Step E. ¹H-NMR (300 MHz, DMSO-d₆): δ 8.02-8.04 (t, 1H), 7.91-7.93 (d,1H), 7.29-7.59 (m, 3H), 7.12-7.29 (m, 1H), 6.88-7.12 (m, 1H), 4.10-4.97(m, 3H), 3.24-3.52 (m, 2H), 1.12-1.38 (m, 9H), 1.00-1.12 (m, 3H); LC/MS:C₂₁H₂₄F₂NO₃PS: m/z 440.1 (M+1).

Cpd 53:[2-(3,4-Difluoro-phenyl)-1-(3-methyl-benzo[b]thiophen-2-yl)ethyl]-phosphonicacid bis-(2,2-dimethyl-propyl) ester. Compound 53 was prepared accordingto the method of Example 1, substituting tri-neopentyl phosphite forCompound 1e of Step D, and substituting 3,4-difluorobenzyl bromide forCompound 1g in Step E. ¹H-NMR (300 MHz, CD₃OD): δ 7.79-7.81 (m, 1H),7.57-7.59 (m, 1H), 7.30-7.33 (m, 2H), 7.00-7.02 (m, 1H), 6.72-6.93 (m,1H), 3.92-4.23 (m, 1H), 3.69-3.75 (m, 3H), 3.54-3.57 (m, 1H), 3.42-3.53(m, 1H), 2.78-3.21 (m, 1H), 2.08-2.09 (d, 3H), 0.865-0.933 (m, 18H);LC/MS: C₂₇H₃₅F₂O₃PS: m/z 508.8 (M+).

Cpd 62:2-(3,4-Difluoro-phenyl)-[1-(3,5-dimethyl-benzo[b]thiophen-2-yl)-ethyl]-phosphonicacid diisopropyl ester. Compound 62 was prepared according to the methodof Example 1, substituting 3,5-dimethyl-benzo[b]thiophene for Compound1a of Step A; substituting triisopropyl phosphite for Compound 1e ofStep D; and substituting 3,4-difluorobenzyl bromide for Compound 1g inStep E. ¹H-NMR (300 MHz, CDCl₃): δ 7.64-7.66 (d, 1H), 7.32 (s, 1H),7.12-7.14 (d, 1H), 6.82-6.91 (m, 2H), 6.69-6.72 (m, 1H), 4.72-4.77 (m,1H), 4.60-4.65 (m, 1H), 3.66-3.75 (m, 1H), 3.41-3.44 (m, 1H), 3.06-3.11(m, 1H), 2.44 (s, 3H), 2.29-2.30 (d, 3H), 1.29-1.32 (m 9H), 1.02-1.04(d, 3H); LC/MS: C₂₄H₂₉F₂O₃PS: m/z 467.2 (M+1).

Cpd 63:[1-Benzo[b]thiophen-2-yl-2-(3,4-difluoro-phenyl)-ethyl]-phosphonic aciddiisopropyl ester. Compound 63 was prepared according to the method ofExample 1, substituting benzo[b]thiophene-2-carbaldehyde for Compound 1bof Step B; substituting triisopropyl phosphite for Compound 1e of StepD; and substituting 3,4-difluorobenzyl bromide for Compound 1g in StepE. ¹H-NMR (300 MHz, DMSO-d₆): δ 7.84-7.86 (m, 1H), 7.70-7.72 (m, 1H),7.16-7.32 (m, 5H), 6.72-7.10 (m, 1H), 4.61-4.65 (m, 1H), 4.47-4.51 (m,1H), 3.90-4.23 (m, 1H), 3.20-3.49 (m, 1H), 2.92-3.20 (m, 1H), 1.20-1.27(m, 9H), 1.01-1.03 (d, 3H); LC/MS: C₂₂H₂₅F₂O₃PS: m/z 438.9 (M+1).

Cpd 78:[1-Benzo[b]thiophen-2-yl-2-(3,4-dichloro-phenyl)-ethyl]-phosphonic aciddiethyl ester. Compound 78 was prepared according to the method ofExample 1, substituting benzo[b]thiophene for Compound 1a of Step A, andsubstituting 3,4-dichlorobenzyl bromide for Compound 1g in Step E.¹H-NMR (300 MHz, DMSO-d₆): δ 7.85-7.87 (d, 1H), 7.71-7.73 (d, 1H),7.55-7.56 (d, 1H), 7.40-7.42 (d, 1H), 7.19-7.32 (m, 4H), 4.18-4.28 (m,1H), 3.87-4.09 (m, 4H), 3.32-3.45 (m, 1H), 3.10-3.19 (m, 1H), 1.21-1.24(t, 3H), 1.10-1.14 (t, 3H); LC/MS: C₂₀H₂₁Cl₂O₃PS: m/z 442.6 (M+1).

Cpd 87: [1-Benzofuran-2-yl-2-(4-fluoro-phenyl)-ethyl]-phosphonic aciddiethyl ester. Compound 87 was prepared according to the method ofExample 1, substituting benzofuran-2-carbaldehyde for Compound 1b ofStep B. ¹H-NMR (300 MHz, DMSO-d₆): δ 7.48-7.53 (m, 2H), 7.11-7.25 (m,4H), 6.97-7.01 (t, 2H), 6.73-6.74 (d, 1H), 4.00-4.10 (m, 5H), 3.19-3.31(m, 2H), 1.21-1.24 (t, 3H), 1.12-1.16 (t, 3H); LC/MS: C₂₀H₂₂FO₄P: m/z377.0 (M+1).

Cpd 92:[1-(5-Chloro-3-methyl-benzo[b]thiophen-2-yl)-2-(3,4-difluorophenyl)-ethyl]-phosphonicacid diisopropyl ester. Compound 92 was prepared according to the methodof Example 1, substituting 5-chloro-3-methyl-benzo[b]thiophene forCompound 1a of Step A; substituting triisopropyl phosphite for Compound1e of Step D; and substituting 3,4-difluorobenzyl bromide for Compound1g in Step E. ¹H-NMR (300 MHz, DMSO-d₆): δ 7.89-7.91 (d, 1H), 7.67-7.68(d, 1H), 7.14-7.32 (m, 3H), 6.95-6.98 (m, 1H), 4.63-4.68 (m, 1H),4.48-4.53 (m, 1H), 4.09-4.18 (m, 1H), 3.34-3.39 (m, 1H), 2.99-3.05 (m,1H), 2.10-2.11 (d, 3H), 1.24-1.27 (m 6H), 1.20-1.22 (d, 3H), 0.962-0.977(d, 3H); LC/MS: C₂₃H₂₆ClF₂O₃PS: m/z 487.0 (M+1).

Cpd 101:[2-(3,4-Difluoro-phenyl)-1-(3-methyl-benzo[b]thiophen-2-yl)ethyl]-phosphonicacid dicyclohexyl ester. Compound 101 was prepared according to themethod of Example 1, substituting tricyclohexyl phosphite for Compound1e of Step D, and substituting 3,4-difluorobenzyl bromide for Compound1g in Step E. ¹H-NMR (300 MHz, DMSO-d₆): δ 7.84-7.86 (m, 1H), 7.58-7.61(m, 1H), 7.24-7.33 (m, 3H), 7.13-7.20 (m, 1H), 6.95-6.97 (m, 1H),4.30-4.40 (m, 2H), 4.09-4.14 (m, 1H), 3.37-3.39 (m, 1H), 2.82-3.10 (m,1H), 2.10-2.11 (d, 3H), 1.80 (m, 3H), 1.15-1.64 (m, 18H); LC/MS:C₂₉H₃₅F₂O₃PS: m/z 532.8 (M+).

Example 2

A. 1-Bromo-3-methyl-butan-2-one. To a solution of 3-methyl-2-butanone(6.0 g; 69.7 mmol), dissolved in MeOH (40 mL), cooled to 0° C., wasadded bromine (3.56 mL; 69.7 mmol), at a rate such that the internaltemperature did not exceed 10° C. The reaction was allowed to stir for45 min at 5-10° C., to which was then added H₂O (20 mL) and the reactionwas stirred for an additional 18 h at ambient temperature. Water wasadded to the reaction mixture, which was then extracted with diethylether. The combined ether extracts were washed sequentially with 10% aq.NaHCO₃, H₂O, and brine, dried over Na₂SO₄, filtered, and the filtratewas evaporated under reduced pressure to afford Compound 2b. ¹H-NMR (300MHz, CDCl₃): δ 3.98 (s, 2H), 2.95-3.02 (m, 1H), 1.10-1.17 (d, 6H).

B. 3-Methyl-1-phenylsulfanyl-butan-2-one. To a solution of thiophenol(2c) (4.44 mL; 43.4 mmol) in diethyl ether (29 mL) was added pyridine(17.2 mL; 0.21 mol), followed by the dropwise addition of a solution ofCompound 2b (7.18 g; 43.5 mmol) in diethyl ether (15 mL), at ambienttemperature, and the reaction was stirred for 72 h. The reaction wasdiluted with EtOAc, washed with 2N HCl, H₂O, brine, dried over Na₂SO₄,filtered and the solvent evaporated under reduced pressure. The cruderesidue was purified by flash column chromatography (SiO₂) eluting witha heptane-EtOAc gradient to afford Compound 2d. ¹H-NMR (300 MHz, CDCl₃):δ 7.18-7.35 (m, 5H), 3.75 (s, 2H), 2.90-2.97 (m, 1H), 1.09-1.10 (d, 6H).

C. 3-Isopropyl-benzo[b]thiophene. To a hot solution (136° C.) of PPA(8.2 g) in chlorobenzene (50 mL) is added a solution of Compound 2d(4.34 g; 22.4 mmol) in chlorobenzene (35 mL). The reaction was stirredat 136° C. for 18 h, cooled to ambient temperature, diluted with EtOAc,quenched with H₂O, and the EtOAc layer was washed with H₂O, brine, driedover Na₂SO₄, filtered and the solvent evaporated under reduced pressure.The crude residue was purified by flash column chromatography (SiO₂),eluting with a heptane-EtOAc gradient to afford Compound 2e. ¹H-NMR (300MHz, DMSO-d₆): δ 7.95-7.97 (m, 1H), 7.83-7.85 (m, 1H), 7.33-7.43 (m,2H), 3.26-3.31 (m, 1H), 1.31-1.33 (d, 6H); LC/MS: C₁₅H₂₂NO₃PS: m/z 328.0(M+1).

D. 3-Isopropyl-benzo[b]thiophene-2-carboxaldehyde. Compound 2f wasprepared following the method described in Example 1, Step A,substituting Compound 2e for Compound 1a.

E. (3-Isopropyl-benzo[b]thiophen-2-yl)-methanol. Compound 2g wasprepared following the method described in Example 1, Step B,substituting Compound 2f for Compound 1b. Purification by flash columnchromatography (SiO₂), eluting with a heptane-EtOAc gradient, affordedCompound 2g. ¹H-NMR (300 MHz, DMSO-d₆): 7.85-7.88 (m, 1H), 7.26-7.34 (m,1H), 5.61-5.64 (t, 1H), 4.76-4.77 (d, 1H), 3.38-3.42 (m, 1H), 1.35-1.37(d, 6H).

F. (3-Isopropyl-benzo[b]thiophen-2-ylmethyl)-phosphonic acid diethylester. Compound 2h was prepared following the method described inExample 1, Steps C and D, substituting Compound 2g for Compound 1c.Purification by flash column chromatography (SiO₂), eluting with aheptane-EtOAc gradient, afforded Compound 2h. ¹H-NMR (300 MHz, CD₃OD): δ7.93-7.95 (d, 1H), 7.75-7.77 (d, 1H), 7.25-7.30 (m, 2H), 4.05-4.13 (m,4H), 3.51-3.56 (d, 2H), 3.43-3.47 (m, 1H), 1.46-1.48 (d, 6H), 1.27-1.31(t, 6H); LC/MS: C₁₆H₂₃O₃PS: m/z 326.9 (M+1).

Cpd 2:[2-(3,4-Difluoro-phenyl)-1-(3-isopropyl-benzo[b]thiophene-2-yl)-ethyl]-phosphonicacid diethyl ester. Compound 2 was prepared following the methoddescribed in Example 1, Step E substituting Compound 2h for Compound 1f,and substituting 3,4-difluorobenzyl bromide for Compound 1g. ¹H-NMR (300MHz, DMSO-d₆): δ 7.82-7.88 (m, 2H), 7.16-7.29 (m, 4H), 6.81-7.06 (m,1H), 3.90-4.11 (m, 5H), 3.14-3.54 (m, 2H), 2.85-3.14 (m, 1H), 0.97-1.31(m, 12H); LC/MS: C₂₃H₂₇F₂O₃PS: m/z 452.9 (M+1).

Following the procedure described above for Example 2 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 19 480.7 480.2

Example 3

A. 3-Cyclopropyl-benzo[b]thiophene-2-carboxylic acid ethyl ester. To asuspension of 60% NaH (0.26 g; 7.74 mmol) in THF (10 mL), at ambienttemperature, was added ethyl thioglycolate (Compound 3a) (0.86 g; 7.14mmol) dropwise, and the reaction was stirred at ambient temperature for30 min. Cyclopropyl-(2-fluoro-phenyl)-methanone (Compound 3b) (0.98 g;5.96 mmol) was added in one-portion. The reaction was allowed to refluxfor 18 h, then cooled, diluted with EtOAc, washed sequentially with 1 NNaOH, H₂O, and brine, dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure. The crude residue was purified byflash column chromatography (SiO₂), eluting with a heptane-EtOAcgradient to afford 0.484 g (33%) of Compound 3c. ¹H-NMR (300 MHz,DMSO-d₆): δ 7.99-8.05 (m, 2H), 7.64-7.75 (m, 1H), 7.32-7.54 (m, 2H),4.31-4.37 (q, 2H), 2.36-2.51 (m, 1H), 1.32-1.36 (t, 3H), 1.08-1.16 (m,4H); LC/MS: C₁₄H₁₄O₂S: m/z 247.1 (M+1).

B. (3-Cyclopropyl-benzo[b]thiophen-2-yl)-methanol. To a solution of 1 Mlithium aluminum hydride-THF (23 mL; 23 mmol), cooled to 0° C., wasadded a solution of Compound 3c (1.88 g; 7.65 mmol) in THF (25 mL)dropwise, to maintain the internal temperature between 0-5° C. Thereaction was allowed to stir an additional 1 h at 0° C. The reaction wasquenched with saturated NH₄Cl, to which was added 3N NaOH. The layerswere separated and the organic phase washed sequentially with H₂O andbrine, dried over Na₂SO₄, filtered, and the filtrate was concentratedunder reduced pressure to afford Compound 3d. ¹H-NMR (300 MHz, DMSO-d₆):δ 3.55-3.74 (m, 2H), 7.34-7.38 (m, 1H), 7.27-7.31 (m, 1H), 5.57-5.60 (t,1H), 4.83-4.85 (m, 2H), 1.75-1.81 (m, 1H), 0.965-0.996 (m, 2H),0.581-0.620 (m, 2H).

C. Cpd 20:[1-(3-Cyclopropyl-benzo[b]thiophene-2-yl)-2-(3,4-difluorophenyl)-ethyl]-phosphonicacid diisopropyl ester. Compound 20 was prepared following the methodsdescribed in Example 1, substituting Compound 3d for Compound 1c in StepC, substituting triisopropyl phosphite for Compound 1e in Step D, andsubstituting 3,4-difluorobenzyl bromide for Compound 1g in Step E.¹H-NMR (300 MHz, CDCl₃): δ 7.83-7.85 (m, 1H), 7.76-7.78 (m, 1H),7.26-7.33 (m, 2H), 6.84-6.91 (m, 2H), 6.70-6.73 (m, 1H), 4.73-4.78 (m,1H), 4.62-4.66 (m, 1H), 4.14-4.24 (m, 1H), 3.41-3.48 (m, 1H), 3.03-3.11(m, 1H), 1.24-1.36 (m, 10H), 0.840-0.976 (m, 5H), 0.644-0.681 (m, 1H),0.49-0.82 (m, 1H); LC/MS C₂₅H₂₉F₂O₃PS: m/z 479.1 (M+1).

Following the procedure described above for Example 3 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 5 479.1 478.2 20 479.1 478.2 29 451.1 450.1 38507.1 506.2 41 465.1 464.1 45 443.1 442.1 65 459.0 458.1 82 455.1 454.184 493.0 492.1 116 493.0 492.1 117 513.2 512.1 119 493.2 492.2 129 465.1480.2

Cpd 41:[1-(3-Cyclobutyl-benzo[b]thiophen-2-yl)-2-(3,4-difluorophenyl)-ethyl]-phosphonicacid diethyl ester. Compound 41 was prepared following the methoddescribed in Example 3, substitutingcyclobutyl-(2-fluorophenyl)-methanone for Compound 3b of Step A. ¹H NMR(300 MHz, CD₃OD): δ 7.93-7.95 (m, 1H), 7.79-7.81 (m, 1H), 7.26-7.33 (m,2H), 6.94-7.04 (m, 2H), 6.82-6.85 (m, 1H), 3.90-4.20 (m, 5H), 3.68 (m,1H), 3.39-3.47 (m, 1H), 3.03-3.25 (m, 1H), 2.54-2.59 (m, 1H), 2.30-2.37(m, 1H), 1.94-2.13 (m, 3H), 1.32-1.36 (t, 3H), 1.14-1.17 (t, 3H); LC/MS:C₂₄H₂₇F₂O₃PS: m/z 465.1 (M+1).

Cpd 45:[2-(3,4-Difluoro-phenyl)-1-(5-fluoro-3-methyl-benzo[b]thiophene-2-yl)-ethyl]-phosphonicacid diethyl ester. Compound 45 was prepared following the methoddescribed in Example 3, substituting 1-(2,5-difluoro-phenyl)-ethanonefor Compound 3b of Step A. ¹H NMR (300 MHz, DMSO-d₆): δ 7.87-7.91 (m,1H), 7.42-7.45 (m, 1H), 7.31-7.36 (m, 1H), 7.14-7.22 (m, 2H), 7.00-7.01(m, 1H), 4.20-4.30 (m, 1H), 4.03-4.08 (m, 2H), 3.87-3.99 (m, 2H),3.35-3.40 (m, 1H), 3.01-3.08 (m, 1H), 2.12-2.13 (m, 3H), 1.22-1.26 (t,3H), 1.09-1.12 (t, 3H); LC/MS C₂₁H₂₂F₃O₃PS: m/z 443.1 (M+1).

Cpd 65:[1-(4-Chloro-3-methyl-benzo[b]thiophen-2-yl)-2-(3,4-difluorophenyl)-ethyl]-phosphonicacid diethyl ester. Compound 65 was prepared following the methoddescribed in Example 3, substituting1-(2-chloro-6-fluorophenyl)-ethanone for Compound 3b of Step A. ¹H NMR(300 MHz, DMSO-d₆): δ 7.85-7.87 (m, 1H), 7.33-7.38 (m, 2H), 7.17-7.27(m, 2H), 7.01 (m, 1H), 4.04-4.11 (m, 1H), 3.91-3.95 (m, 2H), 3.91-3.94(m, 2H), 3.03-3.10 (m, 1H), 2.43-2.49 (d, 3H), 1.23-1.26 (t, 3H),1.10-1.14 (t, 3H); LC/MS: C₂₁H₂₂ClF₂O₃PS: m/z 459.0 (M+1).

Cpd 82:[2-(3,4-Difluoro-phenyl)-1-[6-methoxy-3-methyl-benzo[b]thiophene-2-yl)-ethyl]-phosphonicacid diethyl ester. Compound 82 was prepared following the methoddescribed in Example 3, substituting1-(2-fluoro-4-methoxy-phenyl)-ethanone for Compound 3b of Step A. ¹H NMR(300 MHz, CD₃OD): δ 7.45-7.47 (d, 1H), 7.34-7.35 (m, 1H), 6.87-7.03 (m,4H), 3.90-4.17 (m, 5H), 3.83 (s, 3H), 3.37-3.59 (m, 1H), 2.91-3.16 (m,1H), 2.03-2.04 (m, 3H), 1.31-1.35 (t, 3H), 1.15-1.19 (t, 3H); LC/MS:C₂₂H₂₅F₂O₄PS: m/z 455.1 (M+1).

Cpd 84:[2-(3,4-Difluoro-phenyl)-(3-methyl)-4-trifluoromethyl-benzo[b]thiophen-2-yl)-ethyl]-phosphonicacid diethyl ester. Compound 84 was prepared following the methoddescribed in Example 3, substituting1-(2-fluoro-6-trifluoromethyl-phenyl)-ethanone for Compound 3b of StepA. ¹H NMR (300 MHz, DMSO-d₆): δ 8.14-8.40 (m, 1H), 7.63-8.02 (m, 1H),7.41-7.62 (m, 1H), 7.26-7.41 (m, 1H), 7.11-7.26 (m, 1H), 6.89-7.11 (m,1H), 4.26-4.58 (m, 1H), 4.02-4.22 (m, 2H), 3.74-4.02 (m, 2H), 3.38-3.58(m, 1H), 3.04-3.16 (m, 1H), 2.07-2.30 (s, 3H), 1.15-1.38 (t, 3H),1.03-1.15 (t, 3H); LC/MS: C₂₂H₂₂F₅O₃PS: m/z 493.0 (M+1).

Cpd 117:[1-(6-Chloro-3-cyclopentyl-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)-ethyl]-phosphonicacid diethyl ester. Compound 117 was prepared following the methoddescribed in Example 3, substituting(4-chloro-2-fluoro-phenyl)-cyclopentyl-methanone for Compound 3b of StepA. ¹H NMR (300 MHz, CD₃OD) δ 7.85 (m, 1H), 7.63-7.65 (m, 1H), 7.25-7.28(m, 1H), 7.00-7.04 (m, 2H), 6.83-6.99 (m, 1H), 3.92-4.21 (m, 5H),3.42-3.48 (m, 1H), 3.04-3.24 (m, 2H), 1.62-1.94 (m, 7H), 1.15-1.36 (m,7H); LC/MS: C₂₅H₂₈ClF₂O₃PS: m/z 513.2 (M+1).

Cpd 119:[1-(3-Cyclohexyl-benzo[b]thiophen-2-yl)-2-(3,4-difluorophenyl)-ethyl]-phosphonicacid diethyl ester. Compound 119 was prepared following the methoddescribed in Example 3, substitutingcyclohexyl-(2-fluorophenyl)-methanone for Compound 3b of Step A. ¹H NMR(300 MHz, CD₃OD): δ 7.89-7.91 (m, 1H), 7.78-7.81 (m, 1H), 7.25-7.29 (m,2H), 6.96-7.05 (m, 2H), 6.83-6.86 (m, 1H), 3.92-4.21 (m, 5H), 3.43-3.49(m, 1H), 3.07-3.11 (m, 1H), 2.45 (m, 1H), 1.15-1.85 (m, 17H); LC/MS:C₂₆H₃₁F₂O₃PS: m/z 493.2 (M+1).

Cpd 129:[2-(3,4-Difluoro-phenyl)-1-[3-(2,2-dimethyl-propyl)benzo[b]thiophen-2-yl)-ethyl]-phosphonicacid diethyl ester. Compound 129 was prepared following the methoddescribed in Example 3, substituting1-(2-fluorophenyl)-3,3-dimethyl-butan-1-one for Compound 3b of Step A.¹H NMR (300 MHz, CD₃OD): δ 7.93-7.95 (m, 1H), 7.79-7.81 (m, 1H),7.26-7.33 (m, 2H), 6.94-7.04 (m, 2H), 6.82-6.85 (m, 1H), 3.90-4.20 (m,5H), 3.68 (m, 1H), 3.39-3.47 (m, 1H), 3.03-3.25 (m, 1H), 2.54-2.59 (m,1H), 2.30-2.37 (m, 1H), 1.94-2.13 (m, 3H), 1.32-1.36 (t, 3H), 1.14-1.17(t, 3H); LC/MS: C₂₄H₂₇F₂O₃PS: m/z 465.1 (M+1).

A. 3-Methyl-thieno[2,3-b]pyridine-2-carboxlic acid ethyl ester. To asolution of Compound 4a (0.637 g; 4.1 mmol), dissolved in MeCN (3.0 mL),at ambient temperature, is added TEA (0.743 mL; 5.3 mmol), followed byCompound 3a (0.542 g; 4.5 mmol) and the reaction was heated undermicrowave radiation at 180° C. for 20 min. The crude reaction wasdiluted with EtOAc, washed sequentially with 3N NaOH, H₂O, and brine,dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The crude residue was purified by flash columnchromatography (SiO₂), eluting with a heptane-EtOAc gradient to affordCompound 4b. ¹H-NMR (300 MHz, DMSO-d₆): δ 8.72-8.74 (m, 1H), 8.28-8.42(m, 1H), 7.36-7.67 (m, 1H), 4.21-4.49 (q, 2H), 1.21-1.36 (t, 3H); LC/MS:C₁₁H₁₁NO₂S: m/z 222.0 (M+1).

B. (3-Methyl-thieno[2,3-b]pyridin-2-yl)-methanol. To a solution 1.0 MLAH in THF (8.6 mL), cooled to 0° C., was added a solution of Compound4b (0.632 g; 2.85 mmol), dissolved in THF (10 mL), dropwise, and thereaction was stirred at 0° C. for 2 h. The reaction was quenched withH₂O, extracted with EtOAc, and the organic phase was washed sequentiallywith H₂O and brine, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure to afford Compound 4c.

C. 2-Bromomethyl-3-methyl-thieno[2,3-b]pyridine. To a solution ofCompound 4c (0.210 g; 1.17 mmol), in DCE (3.0 mL), was added thionylbromide (0.182 mL; 2.34 mmol) at ambient temperature. The reaction wasrefluxed for 3 h, cooled, diluted with EtOAc, and washed sequentiallywith 10% NaHCO₃, H₂O, and brine. The organic phase was dried overNa₂SO₄, filtered, and the filtrate was concentrated under reducedpressure to afford Compound 4d.

D. (3-Methyl-thieno[2,3-b]pyridin-2-ylmethyl)-phosphonic aciddiisopropyl ester. To a solution of Compound 4d in toluene (9.0 mL) wasadded triisopropyl phosphite (0.731 mL; 3.51 mmol) and the reaction wasrefluxed for 18 h. The reaction was cooled, concentrated under reducedpressure and the crude residue was purified by reverse-phase semi-prepHPLC, eluting with a 25-45% MeCN—H₂O gradient, to afford Compound 4e.¹H-NMR (300 MHz, DMSO-d₆): δ 8.48-8.50 (m, 1H), 8.08-8.11 (m, 1H),7.39-7.43 (m, 1H), 4.55-4.60 (m, 2H), 3.48-3.53 (d, 2H), 2.23 (s, 3H),2.46-2.50 (d, 3H), 1.86-1.93 (d, 3H); LC/MS: C₁₅H₂₂NO₃PS: m/z 328.0(M+1).

E. Cpd 34:[2-(3,4-Difluoro-phenyl)-1-(3-methyl-thieno[2,3-b]pyridin-2-yl)-ethyl]-phosphonicacid diisopropyl ester. Compound 34 was prepared following the methodsdescribed in Example 1, Step E substituting Compound 4e for Compound 1f,and substituting 3,4-difluorobenzyl bromide for Compound 1g. ¹H-NMR (300MHz, DMSO-d₆): δ 9.27-9.28 (m, 1H), 8.81-8.83 (m, 1H), 8.13-8.19 (m,2H), 7.97-8.02 (m, 1H), 7.81-7.83 (m, 1H), 5.46-5.50 (m, 1H), 5.34-5.38(m, 1H), 4.94-5.02 (m, 1H), 4.17-4.22 (m, 3H), 3.81-3.88 (m, 1H),2.94-2.95 (d, 3H), 2.04-2.09 (m, 9H), 1.82-1.83 (m, 3H); LC/MS:C₂₂H₂₆F₂NO₃PS: m/z 454.1 (M+1).

Following the procedure described above for Example 4 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 3 443.1 442.1 8 443.1 442.1 16 443.1 442.1 34454.1 453.1 43 507.1 506.1 131 412.0 411.1

Cpd 3:[2-(3,4-Difluoro-phenyl)-1-(4-fluoro-3-methyl-benzo[b]-thiophene-2-yl)-ethyl]-phosphonicacid diethyl ester. Compound 3 was prepared following the methoddescribed in Example 4, substituting 1-(2,6-difluoro-phenyl)-ethanonefor Compound 4a of Step A. ¹H NMR (300 MHz, CDCl₃): δ 7.50-7.52 (d, 1H),7.18-7.23 (m, 1H), 6.86-6.97 (m, 3H), 6.75-6.78 (m, 1H), 3.92-4.17 (m,4H), 3.74-3.84 (m, 1H), 3.45-3.51 (m, 1H), 3.05-3.13 (m, 1H), 2.22-2.24(m, 3H), 1.31-1.35 (t, 3H), 1.20-1.24 (t, 3H); LC/MS C₂₁H₂₂F₃O₃PS: m/z443.1 (M+1).

Cpd 8:[2-(3,4-Difluoro-phenyl)-1-(7-fluoro-3-methyl-benzo[b-]thiophene-2-yl)-ethyl]-phosphonicacid diethyl ester. Compound 8 was prepared following the methoddescribed in Example 4, substituting 1-(2,3-difluoro-phenyl)-ethanonefor Compound 4a of Step A. ¹H NMR (300 MHz, CDCl₃): δ 7.44-7.49 (m, 2H),7.05-7.10 (m, 1H), 6.84-6.95 (m, 2H), 6.73-6.76 (m, 1H), 3.93-4.17 (m,4H), 3.72-3.81 (m, 1H), 3.43-3.50 (m, 1H), 3.04-3.13 (m, 1H), 2.03-2.04(d, 3H), 1.30-1.34 (t, 3H), 1.20-1.24 (t, 3H); LC/MS C₂₁H₂₂F₃O₃PS: m/z443.1 (M+1).

Cpd 16:[2-(3,4-Difluoro-phenyl)-1-(6-fluoro-3-methyl-benzo[b]-thiophene-2-yl)-ethyl]-phosphonicacid diethyl ester. Compound 16 was prepared following the methoddescribed in Example 4, substituting 1-(2,4-difluorophenyl)-ethanone forCompound 4a of Step A. ¹H NMR (300 MHz, CDCl₃): δ 7.28-7.25 (m, 2H),6.85-7.03 (m, 3H), 6.74-6.77 (m, 1H), 3.98-4.17 (m, 4H), 3.76-3.86 (m,1H), 3.47-3.53 (m, 1H), 3.07-3.15 (m, 1H), 2.06-2.07 (d, 3H), 1.30-1.33(t, 3H), 1.24-1.27 (t, 3H); LC/MS C₂₁H₂₂F₃O₃PS: m/z 443.1 (M+1).

Cpd 43:[2-(3,4-Difluoro-phenyl)-1-(3-trifluoromethyl-benzo[b]-thiophene-2-yl)-ethyl]-phosphonicacid diisopropyl ester. Compound 43 was prepared following the methoddescribed in Example 4, substituting2,2,2-trifluoro-1-(2-fluorophenyl)-ethanone for Compound 4a of Step A.¹H NMR (300 MHz, CDCl₃): δ 7.79-7.81 (m, 2H), 7.37-7.41 (m, 2H),6.85-6.96 (m, 2H), 6.74-6.77 (m, 1H), 4.74-4.79 (m, 1H), 4.62-4.66 (m,1H), 4.22-4.28 (m, 1H), 3.49-3.55 (m, 1H), 3.09-3.16 (m, 1H), 1.29-1.34(m, 9H), 1.01-1.03 (d, 3H); LC/MS C₂₃H₂₄F₅O₃PS: m/z 507.1 (M+1).

Example 5

A. Cpd 24:[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(3,4-dichloro-phenyl)ethyl]-phosphonicacid diethyl ester. To a solution of Compound 78 of Example 1 (0.36 g;0.814 mmol) in DCE (4.3 mL) was added AcOH (4.3 mL) followed byN-bromosuccinimide (0.188 g; 1.05 mmol) and the reaction was refluxedfor 18 h. The reaction was cooled, diluted with EtOAc, and washed withH₂O and brine. The organic phase was dried over Na₂SO₄, filtered, andthe filtrate was concentrated under reduced pressure. The crude residuewas purified by reverse-phase semi-prep HPLC eluting with a 65% to 85%MeCN/H₂O gradient to afford Compound 24. ¹H NMR (300 MHz, CDCl₃): δ7.75-7.77 (t, 1H), 7.68-7.70 (m, 1H), 7.34-7.42 (m, 2H), 7.18-7.24 (m,2H), 6.89-6.92 (m, 1H), 3.91-4.23 (m, 5H), 3.49-3.55 (m, 1H), 3.09-3.18(m, 1H), 1.30-1.33 (t, 3H), 1.20-1.23 (t, 3H); LC/MS C₂₀H₂₀BrCl₂O₃PS:m/z 522.6 (M+1).

B. Cpd 64:[2-(3,4-Dichloro-phenyl)-1-(3-phenyl-benzo[b]thiophen-2-yl)ethyl]-phosphonicacid diethyl ester. To a solution of Compound 24 (0.266 g; 0.509 mmol),in toluene (2.5 mL) was added 2M aqueous Na₂CO₃ (1.0 mL), phenyl-boronicacid (Compound 5a) (0.124 g; 1.01 mmol) and palladium triphenylphosphine(0.005 g; 0.004 mmol) and the reaction was refluxed for 16 h. At thattime, the reaction was cooled, diluted with EtOAc, and washed with H₂Oand brine. The organic phase was dried over Na₂SO₄, filtered, and thefiltrate was concentrated under reduced pressure. The crude residue waspurified by reverse-phase semi-prep HPLC eluting with a 70% to 90%MeCN/H₂O gradient to afford Compound 64. ¹H NMR (300 MHz, CDCl₃): δ7.82-7.84 (d, 1H), 7.23-7.46 (m, 7H), 7.09-7.11 (d, 2H), 6.90-6.01 (d,1H), 6.65-6.67 (m, 1H), 6.41-6.42 (m, 1H), 4.01-4.20 (m, 4H), 3.72-3.81(m, 1H), 3.02-3.35 (m, 2H), 1.32-1.35 (t, 3H), 1.24-1.28 (t, 3H); LC/MSC₂₅H₂₅Cl₂O₃PS: m/z 518.7 (M+).

Following the procedure described above for Example 5 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 12 472.8 472.1 15 518.7 516.0 24 522.6 519.964 518.7 518.1 93 596.5 593.9 124 501.1 500.1 127 491.1 488.0 143 518.7517/519 144 518.7 519.0 166 515.83 516.9 192 501.0 499.38 193 517.0517.37 194 519.0 517.37 195 603.0 601.83 196 501.0 499.37 197 501.0499.37 198 579.0 578.27 199 579.0 578.27 200 579.0 578.27 205 521.1519.29 206 493.0 491.24 266 473.0/475.0 473.25 267 533.0/535.0 533.8

Cpd 12:[1-(3-Chloro-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)ethyl]-phosphonicacid diisopropyl ester. Compound 12 was prepared from Compound 63(prepared according to Example 1) following the method described inExample 5 and substituting N-bromosuccinimide with N-chlorosuccinimide.¹H NMR (300 MHz, DMSO-d₆): δ 7.99-8.01 (t, 1H), 7.63-7.65 (m, 1H),7.42-7.45 (m, 2H), 7.17-7.20 (m, 2H), 6.79-7.05 (m, 1H), 4.67-4.69 (m,1H), 4.50-4.52 (m, 1H), 3.95-4.28 (m, 1H), 3.25-3.56 (m, 1H), 2.89-3.21(m, 1H), 1.27-1.28 (d, 6H), 1.22-1.23 (d, 3H), 1.00-1.01 (d, 3H); LC/MSC₂₂H₂₄ClF₂O₃PS: m/z 472.8 (M+1).

Cpd 15:[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)ethyl]-phosphonicacid diisopropyl ester; and Cpd 93:[1-Bromo-1-(3-bromo-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)-ethyl]-phosphonicacid diisopropyl ester. Compound 15 was prepared from Compound 63(prepared according to Example 1) following the method described inExample 5. ¹H NMR (300 MHz, DMSO-d₆): δ 7.99-8.02 (m, 1H), 7.61-7.63 (m,1H), 7.42-7.47 (m, 2H), 7.15-7.25 (m, 2H), 6.93-6.94 (m, 1H), 4.66-4.71(m, 1H), 4.48-4.53 (m, 1H), 4.05-4.12 (m, 1H), 3.34-3.43 (m, 1H),2.89-3.13 (m, 1H), 1.27-1.29 (d, 6H), 1.21-1.23 (d, 3H), 0.980-0.995 (d,3H); LC/MS C₂₂H₂₄BrF₂O₃PS: m/z 518.7 (M+1).

Cpd 93 was isolated as a by-product during the purification of Compound15. ¹H NMR (300 MHz, DMSO-d₆): δ 8.09-8.11 (m, 1H), 7.73-7.79 (m, 2H),7.46-7.56 (m, 4H), 5.65-5.69 (m, 1H), 4.57-4.66 (m, 1H), 4.25-4.37 (m,2H), 1.06-1.09 (d, 6H), 0.915-0.930 (d, 3H), 0.765-0.780 (d, 3H); LC/MSC₂₂H₂₃Br₂F₂O₃PS: m/z 596.5 (M+1).

Cpd 127:[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)ethyl]-phosphonicacid diethyl ester. Compound 127 was prepared from Compound 75 (whichwas prepared according to Example 1) following the method described inExample 5. ¹H NMR (300 MHz, DMSO-d₆): δ 7.99-8.01 (m, 1H), 7.62-7.64 (m,1H), 7.41-7.48 (m, 2H), 7.16-7.32 (m, 2H), 6.94-6.98 (m, 1H), 3.90-4.26(m, 5H), 3.41-3.47 (m, 1H), 3.06-3.14 (m, 1H), 1.25-1.28 (t, 3H),1.09-1.13 (t, 3H); LC/MS C₂₀H₂₀BrF₂O₃PS: m/z 491.1 (M+1).

Example 6

A. Isobutyl-phosphinic acid ethyl ester. To a solution of 2.0 M isobutylmagnesium bromide (Compound 6a) in ether (10 mL; 20 mmol), undernitrogen, was added triethyl phosphite (Compound 1e, 4.2 mL; 24.1 mmol),dropwise at ambient temperature, and the reaction was stirred for 6 h atambient temperature. The crude mixture was diluted with EtOAc, washedwith H₂O and brine, dried over Na₂SO₄, filtered, and the filtrate wasevaporated under reduced pressure. The crude residue was purified byflash column chromatography (SiO₂), eluting with a heptane-EtOAcgradient (stain with Ninhydrin) to afford Compound 6b. ¹H NMR (300 MHz,CDCl₃): δ 7.81-7.82 (m, 0.5H, P—H), 6.49-6.50 (m, 0.5H, P—H), 4.01-4.21(m, 2H), 2.09-2.18 (m, 1H), 1.66-1.74 (m, 2H), 1.34-1.38 (m, 3H),1.03-1.07 (d, 6H).

B. Isobutyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)-phosphinic acid ethylester. To a suspension of 60% NaH (0.208 g; 5.21 mmol) in toluene (20mL), cooled to 0° C., was added a solution of Compound 6b (0.837 g; 5.57mmol) in toluene (5 mL), dropwise. The reaction mixture was stirred at0° C. for 30 min, to which was added a solution of Compound 1d (0.662 g;3.71 mmol) in toluene (5 mL), dropwise. The reaction was refluxed for 3h, cooled, diluted with EtOAc, washed with H₂O and brine, dried overNa₂SO₄, filtered, and the filtrate was evaporated under reducedpressure. The crude residue was purified by reverse-phase semi-prep HPLCeluting with a 50% to 70% MeCN—H₂O gradient to afford Compound 6c. ¹HNMR (300 MHz, DMSO-d₆): δ 7.87-7.89 (d, 1H), 7.68-7.70 (d, 1H),7.30-7.39 (m, 2H), 3.89-3.99 (m, 2H), 3.46-3.51 (m, 2H), 2.32-2.33 (d,3H), 1.97-2.00 (m, 1H), 1.63-1.68 (m, 2H), 1.16-1.20 (t, 3H),0.965-0.982 (d, 6H); LC/MS C₁₆H₂₃O₂PS: m/z 311.0 (M+).

C. Cpds 6 and 36:[2-(3,4-Difluoro-phenyl)-1-(3-methyl-benzo[b]thiophene-2-yl)-ethyl]-isobutyl-phosphonicacid ethyl ester. Compounds 6 and 36 were prepared following the methoddescribed in Example 1, Step E, substituting Compound 6c for Compound1f, and substituting 3,4-difluorobenzyl bromide for Compound 1g. Themixture of compounds were purified and separated by reverse-phasesemi-prep HPLC (J-sphere, ODS-H80 column; 100×30 mm I.D.; S-4 μM)eluting with a 60% to 80% MeCN—H₂O gradient to afford diastereomers.

Cpd 6: faster-eluting peak; ¹H NMR (300 MHz, DMSO-d₆): δ 7.85-7.87 (m,1H), 7.59-7.61 (m, 1H), 7.27-7.32 (m, 3H), 7.16-7.18 (m, 1H), 6.82-7.06(m, 1H), 4.06-4.13 (m, 3H), 3.23-3.33 (m, 1H), 2.86-3.09 (m, 1H),2.10-2.11 (d, 3H), 1.76-1.99 (m, 1H), 1.59-1.65 (m, 2H), 1.26-1.30 (t,3H), 0.900-0.933 (t, 6H); LC/MS C₂₃H₂₇F₂O₂PS: m/z 436.8 (M+).

Cpd 36: slower-eluting peak; ¹H NMR (300 MHz, DMSO-d₆): δ 7.85-7.87 (m,1H), 7.59-7.61 (m, 1H), 7.26-7.34 (m, 3H), 7.14-7.21 (m, 1H), 6.96-6.97(m, 1H), 4.08-4.14 (m, 3H), 3.89-3.95 (m, 1H), 3.71-3.77 (m, 1H), 3.33(m, 1H), 2.92-3.09 (m, 1H), 2.11-2.12 (d, 3H), 2.01-2.03 (m, 1H),1.68-1.73 (m, 2H), 1.06-1.09 (t, 3H), 0.976-0.992 (t, 6H); LC/MSC₂₃H₂₇F₂O₂PS: m/z 436.8 (M+).

Following the procedure described above for Example 6 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpds 135 and 136:[2-(3,4-Difluoro-phenyl)-1-(3-methyl-benzo[b]thiophene-2-yl)-ethyl]-[3-(4-methoxy-phenyl)-propyl]-phosphonicacid ethyl ester. Compounds 135 and 136 were prepared by the methoddescribed in Example 6, substituting[3-(4-methoxy-phenyl)-propyl]-(3-methyl-benzo[b]thiophen-2-ylmethyl)-phosphinicacid ethyl ester (prepared according to the procedures described inUnited States patent application US 20050176769) for Compound 6c in StepC. The diastereomers were separated by reverse-phase semi-prep HPLC(J-sphere, ODS-H80 column; 100×30 mm I.D.; S-4 μM) eluting with a 60% to80% MeCN—H₂O gradient.

Cpd 135: faster-eluting peak; ¹H NMR (300 MHz, DMSO-d₆): δ 7.84-7.86 (m,1H), 7.59-7.61 (d, 1H), 7.30-7.34 (m, 3H), 7.15-7.18 (m, 1H), 6.88-6.90(m, 3H), 6.68-6.70 (m, 2H), 4.04-4.11 (m, 3H), 3.66 (s, 3H), 2.84-3.08(m, 3H), 2.43-2.49 (m, 1H), 2.08-2.09 (d, 3H), 1.61-1.63 (m, 4H),1.24-1.28 (t, 3H); LC/MS C₂₉H₃₁F₂O₃PS: m/z 528.7 (M+).

Cpd 136: slower-eluting peak; ¹H NMR (300 MHz, DMSO-d₆): δ 7.72-8.06 (m,1H), 7.47-7.72 (m, 1H), 7.29-7.31 (m, 3H), 7.09-7.23 (m, 1H), 7.00-7.02(m, 3H), 6.75-6.77 (m, 2H), 3.98-4.30 (m, 1H), 3.85-3.98 (m, 1H),3.56-3.85 (m, 4H), 3.17 (m, 1H), 2.81-3.09 (m, 1H), 2.28-2.32 (m, 1H),2.10-2.11 (d, 3H), 1.72-1.73 (m, 4H), 1.07-1.11 (t, 3H); LC/MSC₂₉H₃₁F₂O₃PS: m/z 528.7 (M+).

Cpd 30 and 106:[2-(3,4-Difluoro-phenyl)-1-(3-methyl-benzo[b]thiophene-2-yl)-ethyl]-methyl-phosphonicacid ethyl ester. Compounds 30 and 106 were prepared by the methoddescribed in Example 6, substituting methyl-phosphinic acid ethyl esterfor Compound 6b in Step B. Diastereomers 30 and 106 were separated byflash column chromatography (SiO₂), eluting with a heptane-EtOAcgradient.

Cpd 30: faster-eluting peak; ¹H NMR (300 MHz, CD₃OD): δ 7.78-7.81 (m,1H), 7.58-7.60 (m, 1H), 7.28-7.35 (m, 2H), 6.96-7.06 (m, 2H), 6.86-6.89(m, 1H), 3.93-4.12 (m, 4H), 3.47-3.53 (m, 1H), 3.03-3.11 (m, 1H),2.08-2.09 (d, 3H), 1.54-1.57 (d, 3H), 1.24-1.28 (t, 3H); LC/MSC₂₀H₂₁F₂O₂PS: m/z 394.8 (M+).

Cpd 106: slower-eluting peak; LC/MS C₂₀H₂₁F₂O₂PS: m/z 394.8 (M+).

Example 7

A. 1-Propylphosphinoyl-propane. To a solution of 2.0 M propyl magnesiumchloride (7a) in diethyl ether (58 mL; 116 mmol), under nitrogen andcooled in an ice-bath, was added diethyl phosphate (7b) (5.0 mL; 39mmol), dropwise at a rate to maintain temperature between 20-30° C. Thereaction was allowed to stir at ambient temperature for 1 h, to whichwas added a cold solution of K₂CO₃ (16.0 g; 116 mmol) in H₂O (20 mL),dropwise. The resultant mixture was filtered, washed with EtOH (4×100mL), and the EtOH washes were combined and concentrated under reducedpressure. The resultant residue was taken up in diethyl ether, and asolid was removed by filtration. The filtrate was concentrated underreduced pressure to afford Compound 7c. ¹H NMR (300 MHz, DMSO-d₆): δ7.28 (m, 0.5H, P—H), 6.18 (m, 0.5H, P—H), 1.68-1.76 (m, 4H), 1.48-1.59(m, 4H), 0.972-1.00 (t, 6H).

B. 2-(Dipropyl-phosphinoylmethyl)-3-methylbenzo[b]thiophene. The titleCompound 7d was prepared following the method described in Example 6,Step B substituting Compound 7c for Compound 6b. ¹H NMR (300 MHz,CDCl₃): δ 7.76-7.78 (d, 1H), 7.64-7.66 (d, 1H), 7.32-7.42 (m, 2H),3.52-3.55 (d, 2H), 2.37-2.38 (d, 3H), 1.77-1.87 (m, 4H), 1.62-1.74 (m,4H), 1.03-1.07 (m, 6H), 0.965-0.982 (d, 6H); LC/MS C₁₆H₂₃OPS: m/z 295.1(M+).

C. Cpd 44:2-[2-(3,4-Difluoro-phenyl)-1-(dipropyl-phosphinyl-ethyl]-3-methyl-benzo[b]thiophene.Compound 44 was prepared following the method described in Example 6,Step C, substituting Compound 7d for Compound 6c. ¹H NMR (300 MHz,CDCl₃): δ 7.78-7.81 (m, 1H), 7.54-7.57 (m, 2H), 7.32-7.38 (m, 2H),6.82-6.93 (m, 2H), 6.71-6.74 (m, 1H), 3.67-3.75 (m, 8H), 0.998-1.03 (m,6H); LC/MS C₂₃H₂₇F₂OPS: m/z 421.1 (M+1).

Cpd 42:2-[(3,4-Difluoro-benzyloxy)-(dipropyl-phosphinyl-methyl]-3-methyl-benzo[b]thiophene.Compound 42 was isolated as a by-product during the synthesis ofCompound 44. ¹H NMR (300 MHz, CDCl₃): δ 7.81-7.83 (d, 1H), 7.70-7.72 (d,1H), 7.35-7.43 (m, 2H), 7.12-7.19 (m, 2H), 7.00-7.03 (m, 1H), 5.23-5.26(d, 1H), 4.70-4.73 (d, 1H), 4.35-4.37 (d, 1H), 2.40-2.41 (d, 3H),1.70-1.92 (m, 5H), 1.51-1.61 (m, 3H), 1.03-1.07 (t, 3H), 0.962-1.00 (t,3H); LC/MS C₂₃H₂₇F₂O₂PS: m/z 437.1 (M+1).

Following the procedure described above for Example 7 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 13 464.1 464.2 33 449.2 448.2 42 437.1 436.144 421.1 420.1 123 499.0 496.1 203 515.1 513.43 204 531.0 529.42

Cpd 33:2-[2-(3,4-Difluoro-phenyl)-1-(diisobutyl-phosphinoyl)-ethyl]-3-methyl-benzo[b]thiophene.Compound 33 was prepared following the method described in Example 7,Step A substituting Compound 6a for Compound 7a. ¹H NMR (300 MHz,DMSO-d₆): δ 7.86-7.88 (m, 1H), 7.58-7.60 (m, 1H), 7.13-7.34 (m, 4H),6.92-6.95 (m, 1H), 3.95-3.96 (m, 1H), 3.39-3.42 (m, 1H), 3.01-3.02 (m,1H), 2.08-2.12 (m, 4H), 1.72-1.98 (m, 3H), 1.50-1.55 (m, 2H), 1.05-1.07(d, 6H), 0.867-0.884 (d, 3H), 0.817-0.833 (d, 3H); LC/MS C₂₅H₃₁F₂OPS:m/z 449.2 (M+1).

Cpd 13:2-[(3,4-Difluoro-benzyloxy)-(diisobutyl-phosphinoyl)-methyl]-3-methyl-benzo[b]thiophene.Compound 13 was isolated as a by-product during the synthesis ofCompound 33. ¹H NMR (300 MHz, DMSO-d₆): δ 7.95-7.97 (m, 1H), 7.77-7.79(d, 1H), 7.36-7.49 (m, 4H), 7.17-7.21 (m, 1H), 5.31-5.34 (d, 1H),4.60-4.63 (d, 1H), 4.45-4.48 (d, 1H), 2.38-2.39 (d, 3H), 1.75-1.80 (m,2H), 1.59-1.73 (m, 4H), 1.00-1.01 (d, 3H), 0.954-0.970 (d, 3H),0.901-0.923 (m, 6H); LC/MS C₂₅H₃₁F₂O₂PS: m/z 464.1 (M+1).

Example 8

A.[2-(3,4-Difluoro-phenyl)-1-(3-methyl-benzo[b]thiophen-2-yl)-ethyl]-phosphonicacid monoethyl ester. To a solution of Compound 14 of Example 1 (0.309g; 0.728 mmol) in DMF (20 mL), was added NaN₃ (0.331 g; 5.09 mmol), inone-portion, at ambient temperature. The reaction was stirred at 100° C.for 18 h, cooled, diluted with EtOAc, sequentially washed with 1 N HCl,H₂O, and brine. The organic phase was dried over Na₂SO₄, filtered, andthe filtrate was concentrated under reduced pressure. The crude residuewas purified by reverse-phase semi-prep HPLC eluting with a 40% to 60%MeCN:H₂O gradient to afford Compound 8a. ¹H NMR (300 MHz, CD₃OD): δ7.77-7.79 (m, 1H), 7.56-7.58 (m, 1H), 7.25-7.33 (m, 2H), 6.95-7.01 (m,2H), 6.83-6.86 (m, 1H), 3.86-4.10 (m, 3H), 3.45-3.51 (m, 1H), 3.05-3.13(m, 1H), 2.05-2.06 (d, 3H), 1.22-1.25 (t, 3H); LC/MS C₁₉H₁₉F₂O₃PS: m/z396.7 (M+).

B. Cpd 103:[2-(3,4-Difluoro-phenyl)-1-(3-methyl-benzo[b]thiophen-2-yl)ethyl]-phosphonicacid 2-dimethylamino-ethyl ester ethyl ester. To a solution of Compound8a (0.131 g; 0.463 mmol) in pyridine (4.0 mL), was added MSNT (0.822 g;2.77 mmol), in one portion, at ambient temperature, followed by theaddition of dimethylaminoethanol (Compound 8b) (0.103 mL; 1.02 mmol) andthe reaction was stirred for 48 h at ambient temperature. An additional2.0 equivalents of Compound 8b were added to the reaction mixture, andthe solution was stirred for an additional 72 h at ambient temperature.The reaction was diluted with EtOAc, washed sequentially with 1 N HCl,H₂O, and brine. The organic phase was dried over Na₂SO₄, filtered, andthe filtrate was concentrated under reduced pressure. The crude residuewas purified by reverse-phase semi-prep HPLC eluting with a 30% to 50%MeCN:H₂O gradient to afford Compound 103. ¹H NMR (300 MHz, CD₃OD): δ7.79-7.83 (m, 1H), 7.59-7.63 (m, 1H), 7.31-7.37 (m, 2H), 6.97-7.08 (m,2H), 6.87-6.90 (m, 1H), 4.41-4.45 (m, 1H), 4.01-4.33 (m, 43.24-3.34 (m,2H), 3.12-3.28 (m, 2H), 2.92 (s, 3H), 2.75 (s, 3H), 2.10-2.11 (d, 3H),1.37-1.41 (t, 3H) 1.17-1.20 (m, 3H); LC/MS C₂₃H₂₈F₂NO₃PS: m/z 467.9(M+).

Example 9

Cpd 79:[2-(3,4-Difluoro-phenyl)-1-methyl-1-(3-methyl-benzo[b]-thiophen-2-yl)-ethyl]-phosphonicacid diethyl ester. To a solution of Compound 1f (0.100 g; 0.336 mmol)in THF (1.0 mL), cooled to −78° C., was added a solution of 2.5 Mn-butyllithium-hexanes (0.175 mL; 0.438 mmol), dropwise. The solutionwas allowed to stir at −70° C. for 30 min. At that time, a solution ofiodomethane (0.072 g; 0.507 mmol) in THF (0.5 mL) was added. Thereaction was allowed to stir for 30 min at −70° C. At that time, another1.3 equivalents of 2.5 M n-butyllithium in hexanes (0.175 mL) was addeddropwise, followed by the dropwise addition of a solution of3,4-difluorobenzyl bromide (0.139 g; 0.671 mmol) in THF (1.0 mL). Thereaction was allowed to warm to ambient temperature and stirred for 18h. The reaction was quenched with saturated aqueous NH₄Cl, diluted withEtOAc, and washed with H₂O and brine. The organic phase was dried overNa₂SO₄, filtered, and the filtrate was concentrated under reducedpressure. The crude residue was purified by reverse-phase semi-prepHPLC, eluting with a 45% to 65% MeCN:H₂O gradient to afford Compound 79.¹H NMR (300 MHz, CD₃OD): δ 7.75-7.79 (t, 1H), 7.32-7.42 (m, 2H),6.97-7.04 (m, 1H), 6.85-6.90 (m, 1H), 6.77-6.80 (m, 1H), 4.10-4.16 (m,2H), 3.87-3.96 (m, 2H), 3.63-3.69 (m, 1H), 3.15-3.20 (m, 1H), 2.77-2.78(d, 3H), 1.63-1.67 (d, 3H), 1.28-1.35 (t, 3H), 1.06-1.10 (t, 3H); LC/MSC₂₂H₂₅F₂O₃PS: m/z 438.7 (M+).

Example 10

Cpd 88:[2-(3,4-Difluoro-phenyl)-1-(3-methyl-1,1-dioxo-1H-1λ⁶-benzo-[b]thiophen-2-yl)-ethyl]-phosphonicacid diethyl ester. To a solution of Compound 14 of Example 1 (0.136 g;0.320 mmol) in DMF (3.5 mL) and H₂O (1.7 mL), was added oxone (1.18 g;1.92 mmol), in one portion, at ambient temperature. The reaction wasstirred for 18 h at ambient temperature, at which time the reactionmixture was diluted with EtOAc, and washed with H₂O and brine. Theorganic phase was dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure. The crude residue was purified byreverse-phase semi-prep HPLC, eluting with a 40% to 60% MeCN:H₂Ogradient to afford Compound 88. ¹H NMR (300 MHz, DMSO-d₆): δ 7.76-7.78(m, 1H), 7.57-7.72 (m, 3H), 7.35-7.40 (m, 1H), 7.21-7.28 (m, 1H),7.07-7.09 (m, 1H), 3.99-4.11 (m, 4H), 3.41 (m, 1H), 3.24-3.29 (m, 2H),2.27 (s, 3H), 1.22-1.25 (t, 3H), 1.15-1.18 (t, 3H); LC/MS C₂₁H₂₃F₂O₅PS:m/z 456.7 (M+).

Following the procedure described above for Example 10 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 118 440.9 440.1

Example 11

Cpd 97:[1-(5-Fluoro-benzo[b]thiophene-3-yl)-2-(4-fluoro-phenyl)-ethyl]-phosphonicacid diethyl ester. To a solution of Compound 11a (prepared according tothe procedures described in United States patent application US20050176769) (0.38 g; 1.26 mmol) in THF (2.0 mL) at −70° C. was added a1.6 M solution of n-butyllithium in hexanes (1.0 mL; 1.6 mmol),dropwise. The reaction mixture was allowed to stir at −70° C. for 30min, to which was then added a solution of Compound 1g (0.2 mL; 1.6mmol) in THF (0.7 mL), dropwise. The reaction mixture was allowed toslowly warm to ambient temperature, and stirred for an additional 30 minbefore quenching with a solution of saturated aqueous NH₄Cl (1.0 mL).The mixture was diluted with EtOAc, washed with H₂O and then brine. Theorganic phase was dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby reverse-phase semi-prep HPLC, eluting with a 55% to 75% MeCN—H₂Ogradient to afford Compound 97. ¹H-NMR (300 MHz, CDCl₃): δ 7.70-7.73 (m,1H), 7.58-7.59 (m, 1H), 7.27-7.30 (m, 2H), 6.96-7.09 (m, 3H), 6.76-6.82(m, 2H), 4.03-4.13 (m, 2H), 3.83-3.91 (m, 1H), 3.47-3.69 (m, 3H),3.19-3.28 (m, 1H), 1.26-1.29 (t, 3H), 0.955-0.990 (t, 3H); LC/MS:C₂₀H₂₁F₂O₃PS: m/z 410.9 (M+).

Following the procedure described above for Example 11 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 86 393.9 392.1 97 410.9 410.1 108 485.9 485.1

Example 12

Cpd 128:{2-(3,4-Difluoro-phenyl)-1-[3-(2-fluoro-pyridin-3-yl)benzo[b]thiophen-2-yl]-ethyl}-phosphonicacid diethyl ester. To Compound 127 (prepared according to Example 5)(0.061 g; 0.125 mmol) in a microwave vessel purged with nitrogen wasadded Compound 12a (0.045 g; 0.319 mmol), dioxane (3.0 mL), Cs₂CO₃(0.081 g; 0.249 mmol), and PdCl₂(dppf) (0.012 g; 0.016 mmol). Thereaction mixture was purged with nitrogen and heated under microwaveradiation for 30 minutes at 180° C. The reaction mixture was dilutedwith EtOAc, and washed with H₂O and brine. The organic phase was driedover Na₂SO₄, filtered, and the filtrate was concentrated reducedpressure. The crude reaction mixture was purified by reverse-phasesemi-prep HPLC eluting with a 55% to 75% MeCN/H₂O gradient to affordCompound 128. LC/MS C₂₅H₂₃F₃NO₃PS: m/z 506.1 (M+1).

Following the procedure described above for Example 12 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd 130:{2-(3,4-Difluoro-phenyl)-1-[3-(6-fluoro-pyridin-3-yl)benzo[b]thiophen-2-yl]-ethyl}-phosphonicacid diethyl ester. Compound 130 was prepared from Compound 127(prepared according to Example 5) following the method described inExample 12, substituting 2-fluoropyridyl-5-boronic acid for Compound12a. ¹H NMR (300 MHz, DMSO-d₆): δ 8.01-8.03 (m, 1H), 6.99-7.40 (m, 7H),6.73-6.75 (m, 1H), 4.00-4.13 (m, 4H), 3.26-3.31 (m, 1H), 2.98-3.07 (m,1H), 1.26-1.29 (t, 3H), 1.14-1.17 (t, 3H); LC/MS C₂₅H₂₃F₃NO₃PS: m/z506.1 (M+1).

Example 13

Cpd 132:1-[(3-Bromo-thieno[2,3-b]pyridin-2-yl)-2-(3,4-difluorophenyl)-ethyl]-phosphonicacid diethyl ester. Compound 132 was prepared from Compound 13afollowing the methods described in Example 4, Steps A and B,substituting 2-chloro-3-pyridinecarboxaldehyde for Compound 4a; andfollowing the method described in Example 5, Step A, substitutingCompound 13d for Compound 78. ¹H NMR (300 MHz, CD₃OD): δ 8.54-8.56 (m,1H), 8.02-8.04 (m, 1H), 7.46-7.49 (m, 1H), 6.98-7.13 (m, 3H), 4.04-4.34(m, 5H), 3.50-3.56 (m, 1H), 3.11-3.19 (m, 1H), 1.33-1.36 (t, 3H),1.22-1.26 (t, 3H); LC/MS C₁₉H₁₉BrF₂NO₃PS: m/z 492.0 (M+1).

Following the procedure described above for Example 13 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compound of the presentinvention was prepared:

MS MS Cpd Observed Calc'd 207 520.0 518.36

Example 14

Cpd 77:[2-(Biphenyl-3-yl-1-(3-methyl-benzo[b]thiophen-2-yl)-ethyl]-phosphonicacid diethyl ester. To a solution of Compound 40 of Example 1 (0.111 g;0.237 mmol), in toluene (1.0 mL) was added 2M aqueous Na₂CO₃ (0.474 mL;0.948 mmol), phenyl-boronic acid (Compound 5a) (0.058 g; 0.475 mmol) andpalladium triphenylphosphine (0.0065 g; 0.0043 mmol) and the reactionwas refluxed for 18 h. At that time, the reaction was cooled, dilutedwith EtOAc, and washed with H₂O and brine. The organic phase was driedover Na₂SO₄, filtered, and the filtrate was concentrated under reducedpressure. The crude residue was purified by reverse-phase semi-prep HPLCeluting with a 60% to 80% MeCN/H₂O gradient to afford Compound 77. ¹HNMR (300 MHz, CD₃OD): δ 7.82-7.86 (m, 1H), 7.52-7.56 (m, 1H), 7.30-7.34(m, 3H), 7.09-7.24 (m, 5H), 3.94-4.23 (m, 5H), 3.48-3.54 (m, 1H),3.11-3.20 (m, 1H), 1.94-1.95 (d, 3H), 1.33-1.37 (t, 3H), 1.18-1.21 (t,3H); LC/MS C₂₇H₂₉O₃PS: m/z 464.9 (M+).

Following the procedure described above for Example 14 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd 72:[1-(3-Methyl-benzo[b]thiophen-2-yl)-2-(3-pyridin-4-yl-phenyl)ethyl]-phosphonicacid diethyl ester. Compound 72 was prepared from Compound 40 (preparedaccording to Example 1) following the method described in Example 14,Step A and substituting 4-pyridyl boronic acid for Compound 5a. ¹H NMR(300 MHz, CD₃OD): δ 8.50-8.60 (m, 2H), 7.82-7.86 (m, 2H), 7.40-7.54 (m,3H), 7.25-7.35 (m, 5H), 4.15-4.23 (m, 2H), 3.95-4.12 (m, 2H), 3.53-3.69(m, 1H), 3.12-3.25 (m, 3H), 1.97 (s, 3H), 1.34-1.37 (t, 3H), 1.18-1.22(t, 3H); LC/MS C₂₆H₂₈NO₃PS: m/z 465.8 (M+).

Example 15

A. (3-Bromomethyl-benzo[b]thiophen-2-ylmethyl)-phosphonic acid diethylester. To a solution of Compound 1f of Example 1 (0.215 g; 0.721 mmol)in CCl₄ (3.0 mL) was added N-bromosuccinimide (0.133 g; 0.747 mmol)followed by 2,2′-azobisisobutyronitrile (0.018 g; 0.109 mmol) and thereaction refluxed for 18 h under irradiation. The reaction was cooled,diluted with EtOAc, and washed with H₂O and brine. The organic phase wasdried over Na₂SO₄, filtered, and the filtrate was concentrated underreduced pressure. The crude residue was purified by flash columnchromatography (SiO₂) eluting with a heptane-EtOAc gradient to affordCompound 15a. ¹H NMR (300 MHz, CDCl₃): δ 7.77-7.80 (m, 2H), 7.33-7.45(m, 2H), 4.77-4.80 (s, 2H), 4.06-4.14 (m, 4H), 3.28-3.52 (d, 2H),1.28-1.32 (t, 6H).

B. [1-(3-Dimethylaminomethyl-benzo[b]thiophen-2-ylmethyl)-phosphonicacid diethyl ester. To a solution of Compound 15a (0.139 g; 0.368 mmol)in MeOH (2.0 mL) was added a 2M solution of dimethylamine in methanol(5.0 mL) and the reaction was heated at 65° C. in a pressure tube. Thereaction was cooled, diluted with EtOAc, and washed with 10% NaOH, H₂Oand brine. The organic phase was dried over Na₂SO₄, filtered, and thefiltrate was concentrated under reduced pressure. The crude residue waspurified by flash column chromatography (SiO₂), eluting with aheptane-EtOAc gradient to afford Compound 15b. LC/MS C₁₆H₂₄NO₃PS: m/z341.9 (M+).

C. Cpd 114:[1-(3-Dimethylaminomethyl-benzo[b]thiophen-2-yl)-2-(2-fluoro-phenyl)-ethyl]-phosphonicacid diethyl ester. Compound 114 was prepared following the methoddescribed in Example 1, Step E substituting Compound 15b for Compound 1fand 2-fluorobenzyl bromide for Compound 1g. LC/MS C₂₃H₂₉FNO₃PS: m/z449.9 (M+1).

Example 16

A. Cpd 94: Benzo[b]thiophen-2-ylmethyl-phosphonic acid2,6-dichloro-benzyl ester ethyl ester. To a solution of Compound 16a ofExample 1 (0.138 g, 0.484 mmol) in DMF (1.0 mL) was added 60% NaH (0.019g; 0.726 mmol) and the suspension was stirred at ambient temperature for1 h. 2,6-Dichlorobenzyl bromide (Compound 16b) (0.127 g; 0.532 mmol) wasadded in one-portion and the suspension was stirred at ambienttemperature for 18 h. The reaction was diluted with EtOAc, and washedwith H₂O and brine. The organic phase was dried over Na₂SO₄, filtered,and the filtrate was concentrated under reduced pressure. The cruderesidue was purified by reverse-phase semi-prep HPLC eluting with a 55%to 75% MeCN:H₂O gradient to afford Compound 94. ¹H NMR (300 MHz, CD₃OD):δ 7.75-7.77 (m, 1H), 7.67-7.69 (m, 1H), 7.21-7.41 (m, 6H), 5.32-5.41 (m,2H), 4.10-4.17 (m, 2H), 3.59-3.64 (d, 2H), 1.26-1.30 (t, 3H); LC/MSC₁₈H₁₇Cl₂O₃PS: m/z 416.7 (M+1).

Following the procedure described above for Example 16 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 94 416.7 414.0 104 360.9 360.1 105 380.9 380.0107 364.8 364.1 109 364.8 364.1 110 426.7 424.0 111 347.0 346.1

Cpd 104: Benzo[b]thiophen-2-ylmethyl-phosphonic acid ethyl ester2-methyl-benzyl ester. Compound 104 was prepared following the methoddescribed in Example 16, Step A substituting 2-methylbenzyl bromide forCompound 16b. ¹H NMR (300 MHz, CD₃OD): δ 7.76-7.78 (m, 1H), 7.67-7.69(m, 1H), 7.11-7.33 (m, 7H), 5.09-5.17 (m, 2H), 4.81-4.88 (m, 2H),4.00-4.08 (m, 2H), 2.21-2.32 (s, 3H), 1.21-1.25 (t, 3H); LC/MSC₁₉H₂₁O₃PS: m/z 360.9 (M+).

Cpd 109: Benzo[b]thiophen-2-ylmethyl-phosphonic acid ethyl ester2-fluoro-benzyl ester. Compound 109 was prepared following the methoddescribed in Example 16, Step A substituting 2-fluorobenzyl bromide forCompound 16b. ¹H NMR (300 MHz, CD₃OD): δ 7.76-7.78 (m, 1H), 7.67-7.69(m, 1H), 7.28-7.40 (m, 4H), 7.18-7.19 (m, 1H), 7.07-7.12 (m, 2H),5.12-5.15 (m, 2H), 4.03-4.11 (m, 2H), 3.57-3.62 (d, 2H), 1.23-1.27 (t,3H); LC/MS C₁₈H₁₈FO₃PS: m/z 364.8 (M+).

Example 17

A. 3-Bromo-2-methyl-benzo[b]thiophene. To a mixture of Compound 17a(10.0 g; 67.4 mmol) and anhydrous NaOAc (6.74 g; 82.2 mmol), in AcOH(100 mL), at ambient temperature, was added Br₂, drop-wise, and thereaction mixture was stirred at ambient temperature for 1 h. Thereaction mixture was poured into H₂O, extracted with CHCl₃ severaltimes, and the combined extracts were washed sequentially with H₂O, 1 NNaOH, H₂O, and dried over Na₂SO₄. The mixture was filtered and thesolvent evaporated under reduced pressure to afford Compound 17b. ¹H NMR(400 MHz, DMSO-d₆): δ 7.95-7.97 (m, 1H), 7.64-7.67 (m, 1H), 7.46-7.50(m, 1H), 7.39-7.43 (m, 1H), 2.52 (s, 3H). LC/MS C₉H₇BrS: m/z 227.0 (M+).

B. 3-Bromo-2-bromomethyl-benzo[b]thiophene. To a solution of Compound17b (15.6 g; 69 mmol) in CCl₄ (200 mL) was added N-bromosuccinimide(14.7 g; 83 mmol) and the reaction was refluxed for 24 h. The reactionwas cooled and then concentrated under reduced pressure. The resultantresidue was purified by flash column chromatography (SiO₂) eluting witha heptane-EtOAc gradient to afford Compound 17c.

C. (3-Bromo-benzo[b]thiophen-2-ylmethyl)-phosphonic acid diethyl ester.To a solution of Compound 17c (22.0 g; 72 mmol) in toluene (100 mL) wasadded triethyl phosphite, Compound 1e (38.0 mL; 216.0 mmol) and thereaction was refluxed for 24 h. The reaction mixture was cooled,concentrated under reduced pressure and the resultant residue waspurified by flash column chromatography (SiO₂), eluting with ahexanes-EtOAc gradient to afford of Compound 17d. ¹H-NMR (400 MHz,CDCl₃): δ 8.00-8.02 (d, 1H), 7.70-7.72 (d, 1H), 7.45-7.52 (m, 2H),3.98-4.00 (q, 4H), 3.62-3.68 (d, 2H), 1.19-1.24 (t, 6H); LC/MS:C₁₃H₁₆BrO₃PS: m/z 365.0 (M+1).

D. Cpd 137:[1-(3-Bromo-benzo[b]thiophene-2-yl)-2-(3-chloro-phenyl)-ethyl]-phosphonicacid diethyl ester. To a solution of Compound 17d (0.188 g; 0.518 mmol)in THF (2.0 mL) cooled to −70° C., was added a 1.0 M solution of lithiumbis(trimethylsilyl)amide in THF (0.673 mL; 0.673 mmol), drop-wise. Thereaction mixture was allowed to stir at −70° C. for 30 min, to which wasthen added a solution of Compound 17e (0.138 g; 0.673 mmol) in THF (1.0mL), dropwise. The reaction mixture was allowed to slowly warm toambient temperature, and stirred for an additional 18 h before quenchingwith a solution of saturated aqueous NH₄Cl (1.0 mL). The mixture wasdiluted with EtOAc, washed with H₂O, brine, and dried over Na₂SO₄. Themixture was then filtered, and the filtrate was concentrated underreduced pressure. The resulting residue was purified by reverse-phasesemi-prep HPLC eluting with a 55% to 75% MeCN—H₂O gradient to affordCompound 137. ¹H-NMR (400 MHz, CDCl₃): δ 8.00-8.02 (m, 1H), 7.60-7.64(m, 2H), 7.41-7.51 (m, 4H), 4.21-4.30 (m, 1H), 4.08-4.15 (m, 2H),3.91-4.03 (m, 2H), 3.49-3.55 (m, 1H), 3.16-3.25 (m, 1H), 1.24-1.27 (t,3H), 1.09-1.13 (t, 3H); LC/MS: C₂₀H₂₁BrClO₃PS: m/z 489.0 (M+1).

Following the procedure described above for Example 17 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 137 489.0 487.7 138 541.0 539.3 139 557.0555.8 140 539.0 539.3 141 523.0 521.3 142 540.9 539.3 143 507.0 505.8144 541.0 539.3 145 539.0 537.3 146 540.9 539.3 147 489.0 487.8 148557.0 555.8 149 540.9 571.8 150 572.9 539.3 151 557.0 555.8 152 553.0551.4 153 555.0 553.4 154 523.0 521.3 155 537.0 537.3 156 503.0 501.4157 531.0 529.4 158 503.0 501.4 159 531.0 529.4 160 557.0 555.3 161585.0 583.4 162 503.0 501.4 163 531.0 529.4 164 537.0 535.8 165 565.0563.9 167 539.0 539.3 168 523.0 522.9 169 523.0 522.9 170 505.0 504.9171 573.2 572.9 172 523.0 522.9 173 505.0 504.9 174 523.0 522.9 175505.0 504.9 176 535.2 534.9 177 539.1 539.3 178 539.1 539.3 179 437.1436.9 180 471.1 471.3 181 471.1 471.3 182 515.1 515.8 183 505.0 505.8184 555.0 555.3 185 489.0 489.3 186 489.0 489.3 187 521.1 520.9 188523.0 522.9 189 461.0 461.3 190 533.0 533.8 191 523.1 522.9 201 461.0461.2 234 519.0 517.3 235 519.0 517.3 236 537.0 537.3 237 537.1 537.3238 471.1 470.1 239 471.0 470.1 240 471.0 470.1 241 567.0/569.0 567.4242 567.0/569.0 567.4 243 567.0/569.0 567.4 244 504.0 504.9 245 538.0538.9 246 552.0 552.9 247 498.0 498.9 248 532.0 532.9 249 566.0 567.0250 580.9 580.0 251 526.9 526.0 252 559 558.0 253 489 488.1 254 545.0522.1 (M + Na+) 255 537.0 536.1 256 483.1 482.1 257 486.9 486.0 258504.9 504.0 259 504.8 504.0 260 520.9 520.0 261 588.9 588.0 262 584.8584.0 263 612.7 612.0 264 568.9 568.1 268 583.0/585.0 583.8 269445.0/443.0 443.3 270 493.0/495.0 492.8 271 527.0/529.0 527.3 272461.0/463.0 461.3 273 495.0 494.8 274 511.0/513.0 511.3 275 486.9/489.0487.7 276 461.0/463.0 461.3 277 493.0/495.0 492.8 278 495.0/497.0 494.8279 477.0/479.1 476.8 280 511.0/513.0 511.3 281 495.0/497.0 494.8 282545.0/547.0 544.8 283 509.0/511.0 508.9 284 427.0/429.0 426.8 285477.0/479.0 476.8 286 495.0/497.1 494.8 287 511.0/513.0 511.3 288515.0/516.9 515.8 289 567.0/569.0 567.3 290 443.0/445.0 443.3 291495.0/497.0 494.8 292 507.0/509.1 506.9 293 443.0/445.0 443.3 294495.0/497.0 494.8 295 533.0/534.9 532.2 296 509.0/511.0 508.9 297461.0/463.0 461.3 298 495.0/497.0 494.8 299 455.0/457.0 454.9 300541.0/543.0 540.9 301 521.0/523.0 520.9 302 489.0/491.1 489.3 303489.0/491.0 489.3 304 537.0/539.1 537.0 305 461.0/463.0 461.3 306455.1/457.0 454.9 307 507.0/504.9 505.7 308 534.9/533.0 533.8 309480.0/478.0 478.3 310 520.0/518.0 518.4 311 521.0/519.0 519.3 312477.9/480.0 478.3 313 511.0/513.0 511.3 314 485.0/483.0 483.3 315500.0/498.0 498.3 317 511.0/513.0 511.4 319 513.0/515.0 513.3 320483.0/485.0 483.3 321 483.0/485.0 483.3 326 579.0/581.0 579.4 335567.0/569.0 567.38 336 551.0/549.0 549.39

Cpd 155:[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(4-trifluoromethoxyphenyl)-ethyl]-phosphonicacid diethyl ester. Compound 155 was prepared according to the method ofExample 17, substituting 4-trifluoromethoxy benzyl bromide for Compound17e of Step D. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.76-7.79 (m, 1H), 7.67-7.70(m, 1H), 7.35-7.44 (m, 2H), 7.12 (d, 2H), 7.00 (d, 2H), 3.92-4.28 (m,5H), 3.52-3.60 (m, 1H), 3.12-3.24 (m, 1H), 1.31 (t, 3H), 1.23 (t, 3H);LC/MS C₂₁H₂₁BrF₃O₄PS: m/z 537.0 (M+1).

Cpd 241:[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-phosphonicacid diisopropyl ester. Compound 241 was prepared according to themethod of Example 17, substituting 4-fluoro-3-trifluoromethyl benzylbromide for Compound 17e of Step D. ¹H NMR (300 MHz, DMSO-d₆): δ7.99-8.02 (m, 1H), 7.61-7.63 (m, 1H), 7.40-7.59 (m, 4H), 7.25-7.32 (m,1H), 4.65-4.74 (m, 1H), 4.43-4.63 (m, 1H), 4.09-4.22 (m, 1H), 3.45-3.53(m, 1H), 3.00-3.21 (m, 1H), 1.27-1.33 (d, 6H), 1.14-1.23 (d, 3H),0.98-1.08 (d, 3H); LC/MS C₂₃H₂₄BrF₄O₃PS: m/z 567.0/569.0 (M/M+2).

Cpd 238:[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(4-fluoro-phenyl)-ethyl]-phosphonicacid diethyl ester. Compound 238 was prepared according to the method ofExample 17, substituting 4-fluoro benzyl bromide for Compound 17e ofStep D. ¹H NMR (400 MHz, DMSO-d₆): δ 8.05-7.97 (m, 1H), 7.66-7.58 (m,1H), 7.50-7.39 (m, 2H), 7.17 (dd, 2H), 6.98 (t, 2H), 4.23-3.84 (m, 5H),3.50-3.38 (m, 1H), 3.15-3.01 (m, 1H), 1.26 (t, 3H), 1.11 (t, 3H); LC/MSC₂₀H₂₁BrFO₃PS: m/z 471.1 (M+1); Anal. Calcd for C₂₀H₂₁BrFO₃PS; C, 50.97;H, 4.50. Found: C, 51.01; H, 4.54.

Cpd 234:(S)-[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)-ethyl]-phosphonicacid diisopropyl ester; and Cpd 235:(R)-[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)-ethyl]-phosphonicacid diisopropyl ester. Compound 15 was separated by chiralchromatography using a Chiralpak AD column (1000 g; 1000 Å; 10 μM; 34cm×80 mm; λ=254 nM) eluting with heptane-EtOH to afford Compound 234 andCompound 235.

Cpd 234: ¹H NMR (300 MHz, DMSO-d₆): δ 7.99-8.02 (m, 1H), 7.61-7.63 (m,1H), 7.42-7.45 (m, 2H), 7.17-7.22 (m, 2H), 6.69-7.05 (m, 1H), 4.59-4.83(m, 1H), 4.34-4.53 (m, 1H), 3.90-4.15 (m, 1H), 3.34-3.43 (m, 1H),2.87-3.13 (m, 1H), 1.27-1.29 (d, 6H), 1.21-1.23 (d, 3H), 0.980-0.995 (d,3H); LC/MS C₂₂H₂₄BrF₂O₃PS: m/z 517.0/519.0 (M+1); Anal. Calcd forC₂₂H₂₄BrF₂O₃PS; C, 51.07; H, 4.68; F, 7.34; P, 5.99. Found: C, 50.7; H,4.84; F, 7.12; P, 5.71. [α]_(D) ²⁵+89.8° (c 1.04, MeOH).

Cpd 235: ¹H NMR (300 MHz, DMSO-d₆): δ 8.00-8.02 (m, 1H), 7.61-7.63 (m,1H), 7.40-7.47 (m, 2H), 7.15-7.26 (m, 2H), 6.92-6.94 (m, 1H), 4.64-4.72(m, 1H), 4.46-4.54 (m, 1H), 4.04-4.14 (m, 1H), 3.35-3.45 (m, 1H),3.02-3.11 (m, 1H), 1.27-1.29 (d, 6H), 1.21-1.23 (d, 3H), 0.978-0.993 (d,3H); LC/MS C₂₂H₂₄BrF₂O₃PS: m/z 519.0 (M+1); [α]_(D) ²⁵ −93.3° (c 1.05,MeOH).

Cpd 242:(S)-[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-phosphonicacid diisopropyl ester; and Cpd 243:(R)-[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-phosphonicacid diisopropyl ester. Compound 241 was separated by chiralchromatography using a Chiralpak AD column (500 g; 1000 Å; 20 μM; 17cm×80 mm; λ=220 nM) eluting with 95:5 heptane-EtOH to afford Compound242 and Compound 243.

Cpd 242: ¹H NMR (400 MHz, CDCl₃): δ 7.76-7.78 (m, 1H), 7.65-7.67 (m,1H), 7.32-7.45 (m, 3H), 7.17-7.22 (m, 1H), 6.90-6.95 (m, 1H), 4.78-4.85(m, 1H), 4.63-4.69 (m, 1H), 4.08-4.18 (m, 1H), 3.53-3.55 (m, 1H),3.14-3.17 (m, 1H), 1.33-1.41 (m, 9H), 1.01-1.18 (d, 3H); LC/MSC₂₃H₂₄BrF₄O₃PS: m/z 567.01569.0 (M/M+2); Anal. Calcd for C₂₃H₂₄BrF₄O₃PS;C, 48.69; H, 4.26; F, 13.39. Found: C, 47.95; H, 4.07; F, 13.45. (0.5 eqH₂O); [α]_(D) ²⁵+94.6° (c 1.03, MeOH).

Cpd 243: ¹H NMR (400 MHz, CDCl₃): δ 7.76-7.78 (m, 1H), 7.65-7.67 (m,1H), 7.31-7.38 (m, 3H), 7.17-7.26 (m, 1H), 6.90-6.95 (m, 1H), 4.80-4.85(m, 1H), 4.66-4.79 (m, 1H), 4.11-4.19 (m, 1H), 3.53-3.55 (m, 1H),3.14-3.17 (m, 1H), 1.33-1.41 (m, 9H), 1.10-1.18 (d, 3H); LC/MSC₂₃H₂₄BrF₄O₃PS: m/z 567.0/569.0 (M/M+2); [α]_(D) ²⁵−96.9° (c 1.02,MeOH).

Cpd 239:(S)-[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(4-fluoro-phenyl)ethyl]-phosphonicacid diisopropyl ester; and Cpd 240:(R)-[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(4-fluoro-phenyl)-ethyl]-phosphonicacid diisopropyl ester. Compound 238 was separated by chiralchromatography using a OS-A column (1000 g; 1000 Å; 10 μM; 34 cm×80 mm;λ=254 nM) eluting with hetpante-EtOH (80:20) to afford Compound 239 andCompound 240.

Cpd 239: ¹H NMR (300 MHz, DMSO-d₆): 8.04-7.96 (m, 1H), 7.65-7.58 (m,1H), 7.49-7.39 (m, 2H), 7.17 (dd, 2H), 6.98 (t, 2H), 4.23-3.85 (m, 5H),3.50-3.38 (m, 1H), 3.14-3.00 (m, 1H), 1.26 (t, 3H), 1.11 (t, 3H); LC/MSC₂₀H₂₁BrFO₃PS: m/z 471.0 (M+1); [α]_(D) ²⁵+110.1° (c 1.00, MeOH).

Cpd 240: LC/MS C₂₀H₂₁BrFO₃PS: m/z 471.0 (M+1); [α]_(D) ²⁵−111.1° (C1.00,MeOH).

Cpd 236:(S)-[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(4-trifluoromethoxy-phenyl)-ethyl]-phosphonicacid diisopropyl ester; and Cpd 237:(R)-[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(4-trifluoromethoxy-phenyl)ethyl]-phosphonicacid diisopropyl ester. Compound 155 was separated by chiralchromatography using a Chiralpak AS column (1000 g; 1000 Å; 10 μM; 34cm×80 mm; λ=254 nM) eluting with acetonitrile (100%) to afford Compound236 and Compound 237.

Cpd 236: ¹H NMR (300 MHz, CDCl₃): δ 7.76-7.79 (m, 1H), 7.66-7.69 (m,1H), 7.34-7.43 (m, 2H), 7.10-7.13 (m, 2H), 6.99 (d, 2H), 3.90-4.25 (m,5H), 3.52-3.60 (m, 1H), 3.13-3.24 (m, 1H), 1.31 (t, 3H), 1.22 (t, 3H);LC/MS C₂₁H₂₁BrF₃O₄PS: m/z 537 (M+1); Anal. Calcd for C₂₁H₂₁BrF₃O₄PS; C,46.94; H, 3.94; Br, 14.87; F, 10.61; P, 5.76; S, 5.97. Found: C, 46.56;H, 3.82; Br, 14.96; F, 10.35; P, 5.95; S, 5.35. [α]_(D) ²⁵+92.7° (c1.04, MeOH).

Cpd 237: ¹H NMR (300 MHz, CDCl₃): δ 7.76-7.79 (m, 1H), 7.67-7.70 (m,1H), 7.34-7.43 (m, 2H), 7.10-7.13 (m, 2H), 6.99 (d, 2H), 3.90-4.25 (m,5H), 3.53-3.62 (m, 1H), 3.13-3.24 (m, 1H), 1.31 (t, 3H), 1.22 (t, 3H);LC/MS C₂₁H₂₁BrF₃O₄PS: m/z 537.1 (M+1); [α]_(D) ²⁵−93.7° (c 1.05, MeOH).

Example 18

A.[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)-ethyl]-phosphonicacid. To a solution of Compound 127 of Example 5 (1.25 g; 2.55 mmol) inpyridine (8.0 mL), at ambient temperature, was added trimethylsilylbromide, dropwise, in 3 equal portions (0.55 mL; 4.23 mmol), at 15minute intervals. The reaction was stirred at ambient temperature for 72h, diluted with EtOAc, sequentially washed with 1 N HCl, H₂O, and brine.The organic phase was dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure to afford Compound 18a. ¹H NMR (400MHz, DMSO-d₆): δ 11.42-11.46 (m, 1H), 7.95-7.97 (m, 1H), 7.57-7.59 (m,1H), 7.37-7.45 (m, 2H), 7.10-7.21 (m 2H), 6.86-6.89 (m, 1H), 3.88-3.97(m, 1H), 3.16-3.56 (m, 1H), 2.97-3.05 (m, 1H).

B. Cpd 209:[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)ethyl]-phosphonicacid dibutyl ester. To a solution of Compound 18a (0.050 g; 0.116 mmol)in DMSO (0.5 mL), was added DIEA (0.101 mL; 0.582 mmol), followed by1-bromobutane (Compound 18b), and the reaction was heated at 100° C. for10 min under microwave irradiation. The crude material was purified byreverse-phase semi-prep HPLC eluting with a 70% to 90% MeCN:H₂O gradientto afford Compound 209. ¹H NMR (400 MHz, CD₃OD): δ7.86-7.88 (m, 1H),7.66-7.68 (m, 1H), 7.38-7.45 (m, 2H), 6.97-7.07 (m, 2H), 6.87-6.90 (m,1H), 4.21-4.30 (m, 1H), 3.90-4.05 (m, 4H), 3.45-3.52 (m, 1H), 3.09-3.18(m, 1H), 1.61-1.68 (m, 2H), 1.22-1.52 (m, 6H), 0.890-0.933 (t, 3H),0.755-0.792 (t, 3H); LC/MS C₂₄H₂₈BrF₂O₃PS: m/z 547.0 (M+1).

Following the procedure described above for Example 18 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 209 547.0 545.42 210 639.0 637.48 211 575.1573.47 212 576.9 577.33 213 627.0 (+Na) 605.39

Cpd 212:{[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)ethyl]-methoxycarbonylmethoxy-phosphinoyloxy}-aceticacid methyl ester. Compound 212 was prepared according to the method ofExample 18, substituting toluene for DMSO and bromo acetic-acid methylester for 1-bromobutane of Step B, and heating the reaction for 150° C.for 20 min. ¹H NMR (400 MHz, CD₃OD): δ 7.86-7.88 (m, 1H), 7.66-7.68 (m,1H), 7.40-7.44 (m, 2H), 6.91-7.01 (m, 3H), 4.49-4.83 (m, 5H), 3.71-3.80(m, 7H), 3.29 (m, 1H); LC/MS: C₂₂H₂₀BrF₂O₇PS: m/z 576.9 (M+1).

Example 19

Cpd 214:[2-(3,4-Difluoro-phenyl)-1-(3-phenyl-benzo[b]thiophen-2-yl)ethyl]-phosphonicacid diethyl ester. To a solution of Compound 127 of Example 5 (0.045 g;0.093 mmol), in toluene (1.0 mL) was added 2M aqueous Na₂CO₃ (0.186 mL),phenyl-boronic acid (Compound 5a) (0.023 g; 0.186 mmol) and Pd(Ph₃)₄(0.0034 g; 0.0029 mmol) and the reaction was heated under microwaveirradiation at 150° C. for 10 min. At that time, the reaction wascooled, diluted with EtOAc, and washed with H₂O and brine. The organicphase was dried over Na₂SO₄, filtered, and the filtrate was concentratedunder reduced pressure. The crude residue was purified by reverse-phasesemi-prep HPLC eluting with a 60% to 80% MeCN/H₂O gradient to affordCompound 214. ¹H NMR (400 MHz, DMSO-d₆): δ 7.99-8.01 (d, 1H), 7.10-7.53(m, 8H), 6.81-6.87 (m, 1H), 6.66-6.67 (m, 1H), 6.50 (bs, 1H), 3.92-4.10(m, 4H), 3.59-3.72 (m, 1H), 3.23-3.28 (m, 1H), 2.99-3.06 (m, 1H),1.24-1.28 (t, 3H), 1.12-1.15 (t, 3H); LC/MS C₂₆H₂₅F₂O₃PS: m/z 487.0(M+1).

Following the procedure described above for Example 19 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 214 487.0 486.51 215 503.1 502.51 216 505.0504.50 217 505.0 504.50 218 530.0 529.54 219 545.1 544.55 220 505.0504.50

Cpd 217:{2-(3,4-Difluoro-phenyl)-1-[3-(3-fluoro-phenyl)-benzo[b]thiophen-2-yl)-ethyl]-phosphonicacid diethyl ester. Compound 217 was prepared according to the method ofExample 19, substituting 1,1′-bis(di-tertbutylphosphino)ferrocenepalladium dichloride (PdCl₂(dbpf)) for palladium triphenylphosphine;dioxane for toluene; and heating under microwave irradiation at 110° C.for 10 min in Step A. LC/MS: C₂₆H₂₄F₃O₃PS: m/z 505.0 (M+1).

Example 20

A. 4-Fluoro-benzo[b]thiophene-2-carboxlic acid methyl ester. To asuspension of Compound 20a (5.0 g; 25.4 mmol) in CH₂Cl₂ (20 mL), atambient temperature was added oxalyl chloride (2.44 mL; 28 mmol),followed by catalytic DMF (0.1 mL) and the reaction was allowed to stirat ambient temperature for 18 h. Methanol (20 mL) was added to thereaction mixture, dropwise, and the reaction was allowed to stir anadditional 18 h at ambient temperature. The solvent was evaporated underreduced pressure and the crude residue purified by flash columnchromatography (SiO₂) eluting with a heptane-EtOAc gradient to affordCompound 20b. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.14 (s, 1H), 7.93-7.95 (m,1H), 7.55-7.61 (m, 1H), 7.29-7.33 (m, 1H), 3.91 (s, 3H).

B. (4-Fluoro-benzo[b]thiophen-2-yl)-methanol. To a solution 1.0 M LAH inTHF (37.5 mL), cooled to 0° C., was added a solution of Compound 20b(2.63 g; 12.5 mmol), dissolved in THF (15 mL), dropwise, and thereaction was stirred at 0° C. for 1 h. The reaction was quenched withH₂O, extracted with EtOAc, and the organic phase was washed sequentiallywith H₂O and brine, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude residue was purified byflash column chromatography (SiO₂) eluting with a heptane-EtOAc gradientto afford Compound 20c. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.14 (s, 1H),7.76-7.78 (d, 1H), 7.30-7.35 (m, 2H), 7.13-7.18 (m, 1H), 5.73-5.76 (t,1H), 4.76-4.77 (q, 2H); LC/MS: C₉H₇FOS: m/z 165.0 ((M+1)-H₂O).

C. (4-Fluoro-benzo[b]thiophen-2-ylmethyl)-phosphonic acid diisopropylester. To a solution of Compound 20c (0.71 g; 3.81 mmol), in diethylether (6.5 mL), was added phosphorous tribromide (0.181 mL; 2.42 mmol)at ambient temperature and the reaction was stirred for 1 h. Thereaction was diluted with EtOAc, washed with 10% saturated NaHCO₃ (2×),H₂O, brine, dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure to afford the bromomethylintermediate. This crude material was dissolved in toluene (5 mL), towhich was added triisopropyl phosphite (2.63 mL; 11.44 mmol) and thereaction was refluxed for 72 h. The reaction was cooled, the solventevaporated under reduced pressure and the crude residue purified byflash column chromatography (SiO₂) eluting with a heptane-EtOAcgradient, then by reverse-phase semi-prep HPLC, eluting with a 50-70%MeCN—H₂O gradient, to afford Compound 20d. ¹H-NMR (400 MHz, DMSO-d₆): δ7.76-7.78 (d, 1H), 7.32-7.35 (m, 2H), 7.13-7.18 (m, 1H), 4.56-4.61 (m,2H), 3.58-3.64 (d, 2H), 1.23-1.25 (d, 3H), 1.18-1.19 (d, 3H); LC/MS:C₁₅H₂₀FO₃PS: m/z 331.0 (M+1).

D. Cpd 20e:[2-(3,4-Difluoro-phenyl)-1-(4-fluoro-benzo[b]thiophen-2-yl)-ethyl]-phosphonicacid diisopropyl ester. Compound 20e was prepared following the methodsdescribed in Example 1, Step E substituting Compound 20d for Compound1f, substituting lithium bis(trimethylsilyl)amide for n-butyllithium,and substituting 3,4-difluorobenzyl bromide for Compound 1g. ¹H-NMR (400MHz, CD₃OD): δ 7.58-7.60 (m, 1H), 7.24-7.29 (m, 2H), 6.89-7.09 (m, 4H),4.71-4.76 (m, 1H), 4.57-4.62 (m, 1H), 3.83-3.93 (m, 1H), 3.42-3.48 (m,1H), 3.08-3.17 (m, 1H), 1.29-1.35 (m, 9H), 1.09-1.11 (d, 3H); LC/MS:C₂₂H₂₄F₃O₃PS: m/z 457.0 (M+1).

E. Cpd 221:[1-(3-Bromo-4-fluoro-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)-ethyl]-phosphonicacid diisopropyl ester. Compound 221 was prepared following the methodsdescribed in Example 5, Step A substituting Compound 20e for Compound1f. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.87-7.89 (m, 1H), 7.39-7.44 (m, 1H),7.18-7.27 (m, 4H), 6.93-6.94 (m, 1H), 4.66-4.71 (m, 1H), 4.49-4.53 (m,1H), 4.06-4.16 (m, 1H), 3.40-3.41 (m, 1H), 3.04-3.08 (m, 1H), 1.21-1.30(m, 9H), 1.01-1.02 (d, 3H); LC/MS: C₂₂H₂₃BrF₃O₃PS: m/z 537.0 (M+1).

Following the procedure described above for Example 20 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 221 537.0 535.36 222 587.0 585.36 223 558.92557.31 224 507.0 507.31

Example 21

A. Cpd 225:[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(4-fluoro-3-hydroxyphenyl)-ethyl]-phosphonicacid diethyl ester. To a solution of Compound 156, prepared in Example17 (0.118 g; 0.235 mmol) in CH₂Cl₂ (10 mL), cooled to −40° C., was addeda 1.0M solution of boron tribromide in CH₂Cl₂ (1.4 mL; 1.41 mmol),drop-wise, and the reaction was allowed to warm to 5° C. over 2 h. Thereaction mixture was quenched with saturated NaHCO₃, diluted withCH₂Cl₂, washed with H₂O, dried over Na₂SO₄, filtered, and the filtrateremoved under reduced pressure. The crude residue was purified by flashcolumn chromatography (SiO₂) eluting with a heptane-EtOAc gradient toafford Compound 225. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.79 (s, 1H),7.99-8.01 (m, 1H), 7.62-7.64 (m, 1H), 7.42-7.46 (m, 2H), 6.86-6.89 (m,1H), 6.69-6.71 (m, 1H), 6.37-6.59 (m, 1H), 4.07-4.11 (m, 5H), 2.80-3.12(m, 1H), 1.24-1.27 (t, 3H), 1.08-1.12 (t, 3H); LC/MS: C₂₀H₂₁BrFO₄PS: m/z489.0 (M+1).

Following the procedure described above for Example 21 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 225 489.0 487.32 226 489.0 487.32 227 517.0515.37 228 543.0 541.29 229 571.0 569.35 230 517.0 515.37 231 522.9521.77 232 549.82 551.0 233 537.33 539.0 316 471.0/469.0 469.3 322485.0/486.9 485.3 323 469.0/471.0 469.3 324 469.0/471.0 469.3 325497.0/499.0 497.4

Example 22

A. (4-Trifluoromethanesulfonyl-phenyl)-methanol. To a solution ofCompound 22a (2.08 g, 10.0 mmol) in trifluoroacetic acid (25 mL) wasadded 30% H₂O₂ (5 mL) and the reaction was stirred 5 days. The reactionmixture was diluted with ice-water (125 mL), 10% Pd/C (0.225 g) wasadded, and allowed to stir 18 h. The reaction mixture was extracted withdiethyl ether (3×50 mL), the combined organics washed with saturatedNaHCO₃ (4×50 mL), and treated with solid NaHCO₃ until neutralized. Thelayers were separated, the organic phase treated with 10% Na₂SO₃ (50mL), washed with brine (50 mL), dried over Na₂SO₄ filtered, andevaporated in vacuo to afford Compound 22b. ¹H-NMR (400 MHz, DMSO-d₆): δ8.10 (d, 2H), 7.80 (d, 2H), 5.62 (br s, 1H), 4.70 (s, 2H).

B. 1-Bromo-4-trifluoromethanesulfonyl-benzene. To a solution of Compound22b (2.178 g, 9.05 mmol) in diethyl ether (25 mL) was added PBr₃ (1.3mL, 13.7 mmol) and the reaction was stirred under nitrogen atmospherefor 3 days. The reaction mixture was diluted with diethyl ether (100mL), washed with water (2×50 mL), saturated NaHCO₃ (50 mL), brine (50mL), dried over Na₂SO₄, filtered and the filtrate evaporated underreduced pressure to afford Compound 22c. ¹H-NMR (400 MHz, CDCl₃): 8.03(d, 2H), 7.69 (d, 2H), 4.53 (s, 2H).

Example 23

Cpd 318:[2-(3-Amino-phenyl)-1-(3-bromo-benzo[b]thiophen-2-yl)ethyl]-phosphonicacid diethyl ester. To a solution of Compound 315 (prepared according tothe method in Example 17), (0.5 g; 1.0 mmol) in ethanol (20 mL) wasadded ammonium chloride (0.1 g; 2.0 mmol), aqueous 1 N HCl (20 mL; 20.0mmol), and zinc dust (0.30 g; 4.6 mmol), and the reaction was stirred atambient temperature for 48 h. The reaction was cooled, neutralized withthe dropwise addition of sat'd NaHCO₃ and extracted with ethyl acetate.The organic phase was washed with brine, dried over Na₂SO₄, filtered,and the filtrate was concentrated under reduced pressure. The cruderesidue was purified by reverse-phase semi-prep HPLC eluting with a20-40% MeCN/H₂O gradient to afford Compound 318. ¹H NMR (300 MHz,CDCl₃): δ 7.72-7.78 (m, 1H), 7.65-7.70 (m, 1H), 7.30-7.40 (m, 2H),7.08-7.18 (m, 2H), 6.90-7.00 (m, 2H), 4.14-4.28 (m, 1H), 3.88-4.08 (m,4H), 3.40-3.52 (m, 1H), 3.10-3.22 (m, 1H), 1.14-1.22 (m, 6H); LC/MSC₂₀H₂₃BrNO₃PS: m/z 468.0/470.0 (M/M+2).

Example 24

A. 3-Bromo-2-bromomethyl-indole-1-carboxylic acid tert-butyl ester. To asolution of 3-bromo-2-methyl-indole-1-carboxylic acid tert-butyl ester(Compound 24a) (1.07 g; 3.45 mmol) in carbon tetrachloride (10 mL), atambient temperature, was added n-bromosuccinimide (0.737 g; 4.13 mmol)and the reaction was refluxed for 72 h. The solution was cooled, dilutedwith CH₂Cl₂, washed with H₂O, dried over Na₂SO₄, filtered, and thesolvent evaporated under reduced pressure to afford Compound 24b, whichwas used as is in Step B. ¹H NMR (400 MHz, CDCl₃): δ 8.31 (d, 1H),7.62-7.76 (m, 1H), 7.47-7.62 (m, 1H), 7.36-7.46 (m, 1H), 5.07 (s, 2H),1.73 (s, 9H).

B. 3-Bromo-2-(diisopropoxy-phosphorylmethyl)-indole-1-carboxylic acidtert-butyl ester. To a solution of Compound 24b (1.64 g; 3.45 mmol) intoluene (10 mL) was added triisopropyl phosphite (1.39 mL; 10.3 mmol)and the reaction was refluxed for 24 h. The reaction mixture was cooled,concentrated under reduced pressure and the resultant residue waspurified by flash column chromatography (SiO₂), eluting with ahexanes-EtOAc gradient, followed by reverse-phase semi-prep HPLC elutingwith a 50% to 70% MeCN—H₂O gradient to afford Compound 24c. ¹H-NMR (400MHz, DMSO-d₆: δ 8.06-8.08 (d, 1H), 7.19-7.64 (m, 3H), 4.51-4.53 (m, 2H),3.75-3.80 (d, 2H), 1.66 (s, 9H), 1.20-1.21 (d, 6H), 1.09-1.10 (d, 6H);LC/MS: C₂₀H₂₉BrNO₅P: m/z 476.1 (M+1).

C. Cpd 327:3-Bromo-2-[1-(diisopropoxy-phosphoryl)-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-indole-1-carboxylicacid tert-butyl ester. To a solution of Compound 24c (1.08 g; 2.27 mmol)in THF (10.0 mL) cooled to −70° C., was added a 1.0 M solution oflithium bis(trimethylsilyl)amide in THF (2.50 mL; 2.50 mmol), drop-wise.The reaction mixture was allowed to stir at −70° C. for 30 min, to whichwas then added a solution of 4-fluoro-3-trifluoromethyl benzyl bromide(0.758 g; 2.95 mmol) in THF (10.0 mL), dropwise. The reaction mixturewas allowed to slowly warm to ambient temperature, and stirred for anadditional 18 h before quenching with a solution of saturated aqueousNH₄Cl (1.0 mL). The mixture was diluted with EtOAc, washed with H₂O,brine, and dried over Na₂SO₄. The mixture was then filtered, and thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography (SiO₂) eluting with aheptane-EtOAc gradient, followed by purification by reverse-phasesemi-prep HPLC eluting with a 70% to 90% MeCN—H₂O gradient to affordCompound 327. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.89-7.92 (m, 1H), 7.53-7.67(m, 2H), 7.24-7.44 (m, 4H), 5.19-5.53 (m, 1H), 4.52-4.62 (m, 2H),4.33-4.53 (m, 1H), 3.78-4.07 (m, 1H), 3.34-3.57 (m, 1H), 1.62 (s, 9H),1.15-1.22 (m, 9H), 0.81-0.83 (d, 3H); LC/MS: C₂₈H₃₃BrF₄NO₅P: m/z 652.0(M+1).

D.[1-(3-Bromo-1H-indol-2-yl)-2-(4-fluoro-3-trifluoromethyl-phenyl)ethyl]-phosphonicacid diisopropyl ester. To a solution of Compound 327 (1.06 g; 1.63mmol) in CH₂Cl₂ (0.5 mL) at ambient temperature was addedtrifluoroacetic acid (0.5 mL) and the reaction was allowed to stir for30 min. The reaction mixture was washed with 3N NaOH, extracted withEtOAc, the organic phase washed with H₂O, brine, dried over Na₂SO₄,filtered, and the solvent evaporated under reduced pressure to affordCompound 24d. LC/MS: C₂₃H₂₅BrF₄NO₃P: m/z 552.0 (M+1).

E. Cpd 328:[1-(3-Bromo-1-methyl-1H-indol-2-yl)-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-phosphonicacid diisopropyl ester. To a solution of Compound 24d (25.4 mg; 0.046mmol) in DMF (0.5 mL) at ambient temperature was added 60% NaH (2.5 mg;0.060 mmol) and the suspension was allowed to stir for 30 min.Iodomethane (0.004 mL; 0.055 mmol) was added dropwise and the reactionwas allowed to stir at ambient temperature for 18 h. The mixture wasquenched with 3N NaOH, extracted with EtOAc, the organic extract washedwith H₂O, brine, dried over Na₂SO₄, filtered, and the solvent evaporatedunder reduced pressure. The crude residue was purified by flash columnchromatography (SiO₂) eluting with a heptane-EtOAc gradient to affordCompound 328. LC/MS: C₂₄H₂₇BrF₄NO₃P: m/z 564.0 (M+).

Following the procedure described above for Example 24 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

MS MS Cpd Observed Calc'd 329 592.41 592.0 330 628.0/ 627.05 630.0 331591.0 592.08 332 656.1/ 656.4 658.0

Cpd 330:[1-(3-Bromo-1-methanesulfonyl-1H-indol-2-yl)-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-phosphonicacid diisopropyl ester. Compound 330 was prepared according to themethod of Example 24, substituting methane sulfonyl chloride foriodomethane in Step E. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.87-7.89 (m, 1H),7.53-7.58 (m, 2H), 7.39-7.46 (m, 4H), 5.02-5.11 (m, 1H), 4.57-4.66 (m,2H), 3.82-3.85 (m, 1H), 3.53-3.60 (m, 1H), 3.32-3.37 (m, 3H), 1.19-1.31(m, 9H), 1.03-1.05 (m, 3H); LC/MS: C₂₄H₂₇BrF₄NO₅PS: m/z 628.0/630.0(M+/M+2).

Example 25

A. (E)-[2-(3,4-Difluoro-phenyl)-vinyl]-phosphonic acid diisopropylester. To a suspension of 60% NaH (0.35 g, 8.7 mmol) in THF (8.7 mL), atambient temperature, was added drop-wise diisopropylmethylenediphosphonate (Compound 25a) (3.0 g, 8.7 mmol) with a smallamount of THF to complete the transfer. The addition was completed in 5min, and a small rise in temperature was noted (up from 18° C. to 25°C.). The reaction was stirred for a minimum of 25 min, and as long as 1hr. A solution of 3,4-difluorobenzaldehyde (Compound 25b) (0.96 mL, 8.7mmol) in THF (1 mL) was added over 3 min. The internal reactiontemperature rose to 45° C., and 1 hr at 55° C. The reaction was cooledto room temperature, quenched with H₂O (10 mL), extracted with ether(2×10 mL), ethyl acetate (1×10 mL) and the combined organics were driedover Na₂SO₄, filtered, and the solvent evaporated under reduced pressureto afford a crude oil. The resulting residue was purified by flashcolumn chromatography (SiO₂) eluting with ethyl acetate-CH₂Cl₂ to affordCompound 25c. ¹H-NMR (300 MHz, CDCl₃): δ 7.41-7.11 (m, 4H), 6.18 (t,J=16 Hz, 1H), 4.72 (m, 2H), 1.37 (d, 6H), 1.32 (d, 6H).

B. [1,2-Dibromo-2-(3,4-difluoro-phenyl)-ethyl]-phosphonic aciddiisopropyl ester. To a solution of Compound 25c (1.76 g, 5.78 mmol) incarbon tetrachloride (20 mL), cooled to 0° C., was added bromine (0.16mL; 3.11 mmol) and the mixture was stirred at ambient temperature for 1h. The reaction was cooled to 0° C., sat'd sodium thiosulfate (20 mL)was added, the layers separated, and the aqueous phase extracted withCH₂Cl₂ (2×20 mL). The extracts were combined, dried over MgSO₄,filtered, and the solvent evaporated under reduced pressure. The cruderesidue was purified by flash column chromatography (SiO₂) eluting withEtOAc-CH₂Cl₂ to afford Compound 25d was as a mixture (1.7/1) of isomers.LC/MS: C₁₄H₁₉Br₂F₂O₃P: m/z 463/465/467.0 (M+1, 1:2:1 isotope ratio).

C. (E)-[1-Bromo-2-(3,4-difluoro-phenyl)-vinyl]-phosphonic aciddiisopropyl ester (Cpd 25e) and(Z)-[1-bromo-2-(3,4-difluoro-phenyl)-vinyl]-phosphonic acid diisopropylester. To a solution of Compound 25d (1.67 g; 3.59 mmol) in CH₂Cl₂ (30mL), cooled to 0 to 5° C. (ice bath), was added triethylamine (1.0 mL;7.2 mmol) and the mixture was warmed to 40° C. for 3 h. The reactionmixture was cooled to 7° C., to which was added 1 N HCl (20 mL) and theaqueous layer was extracted with CH₂Cl₂ (2×10 mL). The combined extractswere washed with brine (1×20 mL), dried over MgSO₄, filtered, and thesolvent evaporated under reduced pressure. The crude oil was purified byflash column chromatography (SiO₂) eluting with EtOAc-CH₂Cl₂ to affordCompound 25e (first eluent) and Compound 25f (second eluent).

Cpd 25e: ¹H-NMR (400 MHz, CDCl₃): δ 7.71 (d, J=37 Hz, H—P coupling,E-trans, 1H), 7.47 (m, 1H), 7.22 (m, 1H), 7.13 (m, 1H), 4.72 (m, 2H),1.31 (d, 6H), 1.27 (d, 6H).

Cpd 25f: ¹H-NMR (400 MHz, CDCl₃): δ 7.95 (d, J=37 Hz, H—P coupling,Z-cis, 1H), 7.82 (m, 1H), 7.48 (br d, 1H), 7.19 (m, 1H), 4.73 (m, 2H),1.27 (d, 6H), 1.24 (d, 6H); ¹⁹F-NMR (376 MHz, CDCl₃): δ −133.7, −136.4ppm; ³¹P-NMR (162 MHz, CDCl₃): δ 7.63 ppm. LCMS: C₁₄H₁₈BrF₂O₃P: m/z384/386 (M+1).

(Upon storing at room temperature, Compound 25e isomerized to Compound25f).

D. Cpd 333:(E)-[1-Benzo[b]thiophen-2-yl-2-(3,4-difluoro-phenyl)vinyl]-phosphonicacid diisopropyl ester. To a solution of Compound 25e (759 mg, 1.98mmol) in DME (23 mL), purged with argon gas for 15 min, was addedPd(Ph₃P)₄ (114 mg, 0.1 mmol). The reaction mixture was stirred atambient temperature for 30 min, to which was addedbenzo[b]thiophen-2-ylboronic acid (423 mg, 2.38 mmol), sodium carbonate(210 mg, 1.98 mmol) and H₂O (4.5 mL). The reaction was heated to 70° C.for 2 h, cooled to 45° C., and brine (25 mL) was added. The mixture wasextracted with ethyl acetate (25 mL), and the aqueous layer extractedwith additional ethyl acetate (2×15 mL). The combined organics werewashed with brine (25 mL), dried over MgSO₄, filtered and the solventremoved under reduced pressure. The brown oil was purified by flashcolumn chromatography (SiO₂) eluting with heptane-EtOAc to affordCompound 333. ¹H-NMR (400 MHz, CDCl₃): δ 7.76 (m, 2H), 7.66 (d, J=24 Hz,1H), 7.51-7.30 (m, 2H), 7.10-6.96 (m, 3H), 7.47 (m, 2H), 1.34 (d, 6H),1.28 (d, 6H); ³¹P-NMR (162 MHz, CDCl₃): δ 16.24 ppm. HPLC: 11.256 min,94.4%. Elem. Anal: Calc for C₂₂H₂₃SF₂O₃P: C, 60.54; H, 5.31; F 8.71.found: C, 60.54; H, 5.25; F, 9.06. LCMS: C₂₂H₂₃F₂O₃PS: m/z 437 (M+1); mp93.5-95° C.

E. Cpd 334:(E)-[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(3,4-difluorophenyl)-vinyl]-phosphonicacid diisopropyl ester. To a solution of Cpd 333 (52.4 mg, 0.120 mmol)in DCE (0.5 mL) and AcOH (0.5 mL) was added N-bromosuccinimide (32 mg;0.180 mmol) and the reaction was refluxed for 24 h. The reaction wascooled, concentrated under reduced pressure and the resultant residuewas purified by reverse-phase semi-prep HPLC eluting with a 60% to 80%MeCN—H₂O gradient to afford Compound 334. ¹H-NMR (400 MHz, DMSO-d₆): δ8.10-8.14 (m, 1H), 7.71-7.78 (m, 2H), 7.50-7.59 (m, 2H), 7.27-7.39 (m,2H), 7.04-7.06 (m, 1H), 1.14-1.31 (m, 12H); LCMS: C₂₂H₂₂BrF₂O₃PS: m/z517.0 (M+2).

Example 26 An Alternate Route to Compounds of the Present Invention isPresented Herein

A. (3-Bromo-benzo[b]thiophen-2-ylmethyl)-phosphonic acid diisopropylester. A mixture of Cpd 17c (100 g, 326.8 mmol) and triisopropylphosphite (76.7 mL, 326.8 mmol) were heated at 55° C. for 2 h. Uponcooling, some of Cpd 26a precipitated and was isolated by filtration.The filtrate was evaporated under reduced pressure. The filtered solidsand filtrates were each separately purified by flash columnchromatography (SiO₂) using a heptane-EtOAc gradient. The desiredfractions were combined and slurried in heptane (100 mL) withsonication, filtered, and washed with heptane (3×20 mL). The solid wasfirst air-dried before being transferred to dry in a vacuum oven at 40°C. (20 mm). The desired Compound 26a was obtained as a white solid.

B. Cpd 15:[1-(3-Bromo-benzo[b]thiophen-2-yl)-2-(3,4-difluoro-phenyl)ethyl]-phosphonicacid diisopropyl ester. To a solution of Compound 26a (72 g, 184.0 mmol)in diethyl ether (1.44 L) was added 1 M potassium tert-butoxide in THF(202.4 mL, 202.4 mmol) and the reaction was stirred at ambienttemperature for 15 minutes. To the resulting brown suspension was added3,4-difluorobenzyl bromide (23.6 mL, 184.0 mmol), dropwise, at ambienttemperature, and the reaction was stirred for 16 h. The reaction mixturewas poured into saturated aqueous ammonium chloride (3000 mL), extractedwith EtOAc (2×2500 mL), and the combined organic extracts were driedover MgSO₄, filtered, rinsed with EtOAc (3×50 mL) and the solventevaporated under reduced pressure. The resulting residue was purified byflash column chromatography (SiO₂), eluting with a heptane-EtOAcgradient to afford Compound 15.

Example 27 An Enantioselective Route to Compounds of the PresentInvention

A. Cpd 235: (R)-(3-Bromo-benzo[b]thiophen-2-ylmethyl)-phosphonic aciddiisopropyl ester. To a 5 mL vial with a small stir bar was addedCompound 26a (80 mg, 0.20 mmol) in toluene (1.2 mL),(R,R)-2,6-bis(3,4,5-trifluorophenyl)-3,3′,5,5′-tetrahydro-4,4′-spirobi[dinaphtho[2,1-c:1′,2′-e]azepin]-4-iumbromide (5 mg, 0.005 mmol) and 50% KOH (291 mg KOH in 0.29 mL H₂O) andthe reaction mixture was stirred vigorously at 0° C. Compound 26b (28μL, 0.22 mmol) was added via syringe over 1 min, and vigorously stirredfor at 0° C. for 3.5 hr. An additional portion of Compound 26b (14 μL,0.11 mmol) was added, and the reaction stirred at ambient temperaturefor 60 h. The reaction was worked up by separation of the toluene layer,and neutralization of the aqueous layer by addition of HCl (1 N, 1 mL).The aqueous layer was extracted with CH₂Cl₂ (3×1 mL), and the combinedorganic layers were dried over Na₂SO₄, filtered and the solventevaporated under reduced pressure. The crude residue was purified byflash column chromatography (SiO₂) eluting with an EtOAc-CH₂Cl₂ gradientto afford Compound 235. The enantiomeric excess was determined using aChiralpak AD column (20% IPA hex, 254 nm). The (S)-isomer (Compound 234)eluted at 5.74 min, 13.9%, and the (R)-isomer (Compound 235) eluted at7.61 min, 81.5%. The % ee was 68%.

B. Cpd 234: (S)-(3-Bromo-benzo[b]thiophen-2-ylmethyl)-phosphonic aciddiisopropyl ester. To a 5 mL vial equipped with a small stir bar wasadded Compound 26a (80 mg, 0.20 mmol), toluene (1.2 mL),(S,S)-2,6-bis(3,4,5-trifluorophenyl)-3,3′,5,5′-tetrahydro-4,4′-spirobi[dinaphtho[2,1-c:1′,2′-e]azepin]-4-iumbromide (5 mg, 0.005 mmol) and 50% KOH (291 mg KOH in 0.29 mL water) andthe reaction mixture was stirred vigorously at 0° C. Compound 26b (28μL, 0.22 mmol) was added dropwise via syringe over 30 sec, and assay ofthe reaction was performed at 30 min using chiral HPLC. The analysisrevealed the ratios by HPLC (normalized to 100) to be 20.9% of theCompound 234, 2.6% of the Compound 235, and 74.6% of Compound 26aremaining. The % ee was calculated to be 77%.

Absolute Stereochemistry Determination

The absolute stereochemistry of Compound 234 was determined usingVibrational Circular Dichroism techniques (VCD; BioTools, Inc.). Thecomparison of the experimental VCD data with ab initio DFT calculationsconclude that the assignment of the absolute stereochemistry of Compound234 was (S). By analogy, the absolute stereochemistry of Compound 236,Compound 239, and Compound 242 were assigned (S)-stereochemistry, andCompound 235, Compound 237, Compound 240 and Compound 243 were assigned(R)-stereochemistry.

Using the methods described in the schemes and specific examples, andadaptations thereof, compounds of Formula (Ia) wherein R₃ is H, shown inTable 1, were prepared.

TABLE 1

Formula (Ia) Cpd A W R₄ X R₁ R₂ L B  1 benzo C(R₄) methyl S isopropylisopropyl CH₂ 3,4-difluoro- oxy oxy phenyl  2 benzo C(R₄) i-propyl Sethoxy ethoxy CH₂ 3,4-difluoro- oxy oxy phenyl  3 4-fluoro C(R₄) methylS ethoxy ethoxy CH₂ 3,4-difluoro- benzo phenyl  4 benzo C(R₄) methyl Sethoxy ethoxy CH₂ 3-chloro- phenyl  5 benzo C(R₄) cyclo S ethoxy ethoxyCH₂ 3,4-difluoro- pentyl phenyl Diast. benzo C(R₄) methyl S ethoxyisobutyl CH₂ 3,4-difluoro-  6 phenyl  7 benzo C(R₄) methyl S ethoxyethoxy CH₂ 3-fluoro- phenyl  8 7-fluoro C(R₄) methyl S ethoxy ethoxy CH₂3,4-difluoro- benzo phenyl  9 benzo C(R₄) methyl O ethoxy ethoxy CH₂3,4-difluoro- phenyl  10 benzo C(R₄) methyl S ethoxy ethoxy CH₂2,3-difluoro- phenyl  11 benzo C(R₄) methyl O isopropyl isopropyl CH₂3,4-difluoro- oxy oxy phenyl  12 benzo C(R₄) chloro S isopropylisopropyl CH₂ 3,4-difluoro- oxy oxy phenyl  13 benzo C(R₄) methyl Sisobutyl isobutyl OCH₂ 3,4-difluoro- phenyl  14 benzo C(R₄) methyl Sethoxy ethoxy CH₂ 3,4-difluoro- phenyl  15 benzo C(R₄) bromo S isopropylisopropyl CH₂ 3,4-difluoro- oxy oxy phenyl  16 6-fluoro C(R₄) methyl Sethoxy ethoxy CH₂ 3,4-difluoro- benzo phenyl  17 benzo C(R₄) methyl Sethoxy ethoxy CH₂ 3,5-difluoro- phenyl  18 benzo C(R₄) methyl S ethoxyethoxy CH₂ 3-methyl- phenyl  19 benzo C(R₄) i-propyl S isopropylisopropyl CH₂ 3,4-difluoro- oxy oxy phenyl  20 benzo C(R₄) cyclo Sisopropyl isopropyl CH₂ 3,4-difluoro- propyl oxy oxy phenyl  21 benzoC(R₄) methyl S ethoxy ethoxy CH₂ 3,4-dichloro- phenyl  22 benzo C(R₄)methyl S ethoxy ethoxy CH₂ 2-fluoro- phenyl  23 benzo C(R₄) methyl Sethoxy ethoxy CH₂ 2-fluoro-3- chloro- phenyl  24 benzo C(R₄) bromo Sethoxy ethoxy CH₂ 3,4-dichloro- phenyl  25 benzo N na S isopropylisopropyl CH₂ 3,4-difluoro- oxy oxy phenyl  26 benzo C(R₄) methyl Sethoxy ethoxy CH₂ 2-methyl- phenyl  27 benzo C(R₄) methyl S ethoxyethoxy CH₂ 2-chloro-4- fluoro- phenyl  28 benzo C(R₄) methyl S ethoxyethoxy CH₂ 2-chloro-3,5- difluoro- phenyl  29 benzo C(R₄) cyclo S ethoxyethoxy CH₂ 3,4-difluoro- propyl phenyl Diast. benzo C(R₄) methyl Sethoxy methyl CH₂ 3,4-difluoro-  30 phenyl  31 benzo C(R₄) methyl Sethoxy ethoxy CH₂ 3- trifluoromethyl- 4-fluoro- phenyl  32 benzo C(R₄)methyl S ethoxy ethoxy CH₂ 3-methoxy- phenyl  33 benzo C(R₄) methyl Sisobutyl isobutyl CH₂ 3,4-difluoro- phenyl  34 (2,3-b) C(R₄) methyl Sisopropyl isopropyl CH₂ 3,4-difluoro- pyridin-2- oxy oxy phenyl yl  35benzo C(R₄) methyl S ethoxy ethoxy CH₂ 2,3-dichloro- phenyl Diast. benzoC(R₄) methyl S ethoxy isobutyl CH₂ 3,4-difluoro-  36 phenyl  37 benzoC(R₄) methyl S ethoxy ethoxy CH₂ 2-fluoro-3- trifluoromethyl- yl-phenyl 38 benzo C(R₄) cyclo S isopropyl isopropyl CH₂ 3,4-difluoro- pentyl oxyoxy phenyl  39 benzo C(R₄) H S ethoxy ethoxy CH₂ 3-trifluoromethyl-phenyl  40 benzo C(R₄) methyl S ethoxy ethoxy CH₂ 3-bromo- phenyl  41benzo C(R₄) cyclobutyl S ethoxy ethoxy CH₂ 3,4-difluoro- phenyl  42benzo C(R₄) methyl S n-propyl n-propyl OCH₂ 3,4-difluoro- phenyl  43benzo C(R₄) trifluoro S isopropyl isopropyl CH₂ 3,4-difluoro- methyl oxyoxy phenyl  44 benzo C(R₄) methyl S n-propyl n-propyl CH₂ 3,4-difluoro-phenyl  45 5-fluoro C(R₄) methyl S ethoxy ethoxy CH₂ 3,4-difluoro- benzophenyl  46 benzo C(R₄) methyl S ethoxy ethoxy CH₂ naphthalen- 2-yl  47benzo C(R₄) methyl S ethoxy ethoxy CH₂ 2,5-dichloro- phenyl  48 benzoC(R₄) methyl S ethoxy ethoxy CH₂ 2-chloro- phenyl  49 benzo C(R₄) methylS ethoxy ethoxy CH₂ 3-trifluoro methyl- 4-chloro- phenyl  50 benzo C(R₄)methyl S ethoxy ethoxy CH₂ 4-fluoro- phenyl  51 benzo C(R₄) H S ethoxyethoxy CH₂ 4-fluoro- phenyl  52 benzo C(R₄) methyl S ethoxy ethoxy CH₂3-trifluoro methyl- phenyl  53 benzo C(R₄) methyl S 2,2- 2,2- CH₂3,4-difluoro- dimethyl- dimethyl- phenyl propyl propyl  54 benzo C(R₄)methyl S ethoxy ethoxy CH₂ 2,6-dichloro- phenyl  55 benzo C(R₄) methyl Sethoxy ethoxy CH₂ 4-trifluoro methoxy- phenyl  56 benzo C(R₄) methyl Sethoxy ethoxy CH₂ 3-fluoro-5- trifluoro methyl- phenyl  57 benzo C(R₄)methyl S ethoxy ethoxy CH₂ 3-trifluoro methoxy- phenyl  58 benzo C(R₄) HS ethoxy ethoxy CH₂ 3-fluoro-4- trifluoro methyl- phenyl  59 benzo C(R₄)methyl S ethoxy ethoxy CH₂ 2-trifluoro methyl- phenyl  60 benzo C(R₄)methyl S ethoxy ethoxy CH₂ 2-fluoro-3- methyl-6- chloro- phenyl  61benzo C(R₄) methyl S ethoxy ethoxy CH₂ 2-trifluoro methoxy- phenyl  625-methyl- C(R₄) methyl S isopropyl isopropyl CH₂ 3,4-difluoro- benzo oxyoxy phenyl  63 benzo C(R₄) H S isopropyl isopropyl CH₂ 3,4-difluoro- oxyoxy phenyl  64 benzo C(R₄) phenyl S ethoxy ethoxy CH₂ 3,4-dichloro-phenyl  65 4-chloro- C(R₄) methyl S ethoxy ethoxy CH₂ 3,4-dichloro-benzo phenyl  66 benzo C(R₄) methyl S ethoxy ethoxy CH₂ 2-bromo- phenyl 67 benzo C(R₄) methyl S ethoxy ethoxy CH₂ 2-fluoro-5- trifluoro-methyl- phenyl  68 benzo C(R₄) H S ethoxy ethoxy CH₂ 4- trifluoro-methyl- phenyl  69 benzo C(R₄) H S isopropyl isopropyl CH₂ 3- oxy oxytrifluoro methyl- phenyl  70 benzo C(R₄) H S ethoxy ethoxy CH₂ 4-bromo-phenyl  71 benzo C(R₄) methyl S ethoxy ethoxy CH₂ 5-chloro-benzo[1,3]dioxol- 6-yl  72 benzo C(R₄) methyl S ethoxy ethoxy CH₂3-(pyridin-4- yl)-phenyl  73 benzo C(R₄) methyl S ethoxy ethoxy CH₂2-fluoro-3- chloro-5- trifluoro methyl- phenyl  74 benzo C(R₄) H Sethoxy ethoxy CH₂ phenyl  75 benzo C(R₄) H S ethoxy ethoxy CH₂3,4-difluoro- phenyl  76 benzo C(R₄) methyl S ethoxy ethoxy CH₂2,4-dichloro- 5-fluoro- phenyl  77 benzo C(R₄) methyl S ethoxy ethoxyCH₂ 3-biphenyl  78 benzo C(R₄) H S ethoxy ethoxy CH₂ 3,4-dichloro-phenyl  80 benzo C(R₄) H S ethoxy ethoxy CH₂ 2-fluoro- phenyl  81 benzoC(R₄) methyl S ethoxy ethoxy CH₂ 2-chloro-3- trifluoro methyl- phenyl 82 6- C(R₄) methyl S ethoxy ethoxy CH₂ 3,4-dichloro- methoxy- phenylbenzo  83 benzo C(R₄) H S ethoxy ethoxy CH₂ naphthalen- 2-yl  844-trifluoro C(R₄) methyl S ethoxy ethoxy CH₂ 3,4-difluoro- methyl phenylbenzo  85 benzo C(R₄) H S ethoxy ethoxy CH₂ 2-chloro- phenyl  87 benzoC(R₄) H O ethoxy ethoxy CH₂ 4-fluoro- phenyl  88 benzo C(R₄) methyl SO₂ethoxy ethoxy CH₂ 3,4-difluoro- phenyl  89 benzo C(R₄) H S ethoxy ethoxyCH₂ 2-methyl- phenyl  90 benzo C(R₄) H S ethoxy ethoxy CH₂ benzothio-phen-2-yl  91 benzo C(R₄) methyl S ethoxy ethoxy CH₂ 4-trifluoro methyl-phenyl  92 5-chloro- C(R₄) methyl S isopropyl isopropyl CH₂3,4-difluoro- benzo oxy oxy phenyl  94 benzo C(R₄) H S ethoxy 2,6-absent H dichloro- phenyl methoxy  95 benzo C(R₄) H S ethoxy ethoxy CH₂2,6-dichloro- phenyl  96 benzo C(R₄) H S ethoxy ethoxy CH₂ 3,5-trifluoromethyl- phenyl  98 benzo C(R₄) H S ethoxy ethoxy CH₂ 2-chloro-4- fluoro-phenyl  99 benzo C(R₄) methyl S ethoxy ethoxy CH₂ 2-chloro-5- trifluoromethyl- phenyl 100 benzo C(R₄) H S ethoxy ethoxy CH₂ 2,3-dichloro-phenyl 101 benzo C(R₄) methyl S cyclohexyl- cyclohexyl- CH₂3,4-difluoro- oxy oxy phenyl 102 benzo C(R₄) H S ethoxy ethoxy CH₂2-trifluoro methyl- phenyl 103 benzo C(R₄) methyl S ethoxy 2-(N,N- CH₂3,4-difluoro- dimethyl phenyl amino)- ethoxy 104 benzo C(R₄) H S ethoxy2-methyl- absent H phenyl- methoxy 105 benzo C(R₄) H S ethoxy 2-chloro-absent H phenyl methoxy Diast. benzo C(R₄) methyl S ethoxy methyl CH₂3,4-difluoro- 106 phenyl 107 benzo C(R₄) H S ethoxy 4-fluoro- absent Hphenyl methoxy 109 benzo C(R₄) H S ethoxy 2-fluoro- absent H phenylmethoxy 110 benzo C(R₄) H S ethoxy 2-bromo- absent H phenyl methoxy 111benzo C(R₄) H S ethoxy phenyl- absent H methoxy 112 benzo C(R₄) H Sethoxy ethoxy CH₂ 5-chloro- benzo[1,3] dioxol-6-yI 113 benzo C(R₄)methyl S ethoxy ethoxy CH₂ 2,5-di- trifluoro methyl- phenyl 114 benzoC(R₄) N,N- S ethoxy ethoxy CH₂ 2-fluoro- dimethyl phenyl amino- phenyl115 benzo C(R₄) methyl S ethoxy ethoxy CH₂ 2-biphenyl 116 7-trifluoroC(R₄) methyl S ethoxy ethoxy CH₂ 3,4-difluoro- methyl- phenyl benzo 1176-chloro- C(R₄) cyclo S ethoxy ethoxy CH₂ 3,4-difluoro- benzo pentylphenyl 118 benzo C(R₄) methyl S(O) ethoxy ethoxy CH₂ 3,4-difluoro-phenyl 119 benzo C(R₄) cyclohexyl S ethoxy ethoxy CH₂ 3,4-difluoro-phenyl 120 benzo C(R₄) H O isopropyl isopropyl CH₂ 3,4-difluoro- oxy oxyphenyl 121 benzo C(R₄) H S isopropyl isopropyl CH₂ 3,5-difluoro- oxy oxyphenyl 122 benzo C(R₄) H S isopropyl isopropyl CH₂ 2,3-difluoro- oxy oxyphenyl 123 benzo C(R₄) bromo O s-butyl s-butyl CH₂ 3,4-difluoro- phenyl124 benzo C(R₄) bromo O isopropyl isopropyl CH₂ 3,4-difluoro- oxy oxyphenyl 125 benzo C(R₄) H S isopropyl isopropyl CH₂ 3- oxy oxytrifluorometh yl-4-fluoro- phenyl 126 benzo C(R₄) H S isopropylisopropyl CH₂ 2-fluoro-3- oxy oxy chloro-5- trifluoro methyl- phenyl 127benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3,4-difluoro- phenyl 128 benzoC(R₄) 2-fluoro- S ethoxy ethoxy CH₂ 3,4-difluoro- pyridin-3- phenyl yl129 benzo C(R₄) 2,2- S ethoxy ethoxy CH₂ 3,4-difluoro- dimethyl- phenylpropyl 130 benzo C(R₄) 2-fluoro- S ethoxy ethoxy CH₂ 3,4-difluoro-pyridin-5- phenyl propyl 131 (2,3-b) C(R₄) H S ethoxy ethoxy CH₂3,4-difluoro- pyridin-2- phenyl yl 132 (2,3-b) C(R₄) bromo S ethoxyethoxy CH₂ 3,4-difluoro- pyridin-2- phenyl yl 133 benzo C(R₄) H Sisopropyl isopropyl CH₂ 3-fluoro- oxy oxy phenyl 134 benzo C(R₄) H Sisopropyl isopropyl CH₂ 3-chloro- oxy oxy phenyl Diast. benzo C(R₄)methyl S ethoxy 3-(4- CH₂ 3,4-difluoro- 135 methoxy- phenyl phenyl)-propyl Diast. benzo C(R₄) methyl S ethoxy 3-(4- CH₂ 3,4-difluoro- 136methoxy- phenyl phenyl)- propyl 137 benzo C(R₄) bromo S ethoxy ethoxyCH₂ 3-chloro- phenyl 138 benzo C(R₄) bromo S ethoxy ethoxy CH₂4-fluoro-3- trimethyl- phenyl 139 benzo C(R₄) bromo S ethoxy ethoxy CH₂4-chloro-3- trifluorometh yl-phenyl 140 benzo C(R₄) bromo S ethoxyethoxy CH₂ 3-fluoro-5- trifluorometh yl-phenyl 141 benzo C(R₄) bromo Sethoxy ethoxy CH₂ 3-trifluoro methyl- phenyl 142 benzo C(R₄) bromo Sethoxy ethoxy CH₂ 2-fluoro-3- trifluoro methyl- phenyl 143 benzo C(R₄)bromo S ethoxy ethoxy CH₂ 2-fluoro-3- chloro- phenyl 144 benzo C(R₄)bromo S ethoxy ethoxy CH₂ 3-fluoro-4- trifluoro methyl- phenyl 145 benzoC(R₄) bromo S ethoxy ethoxy CH₂ 3-trifluoro methoxy- phenyl 146 benzoC(R₄) bromo S ethoxy ethoxy CH₂ 2-fluoro-5- trifluoro methyl- phenyl 147benzo C(R₄) bromo S ethoxy ethoxy CH₂ 2-chloro- phenyl 148 benzo C(R₄)bromo S ethoxy ethoxy CH₂ 2-chloro-5- trifluoro methyl- phenyl 149 benzoC(R₄) bromo S ethoxy ethoxy CH₂ 3-chloro-4- trifluoro methoxy- phenyl150 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 2-fluoro-4- trifluoro methyl-phenyl 151 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 2-chloro-3- trifluoromethyl- phenyl 152 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3-trifluoromethyl-4- methoxy- phenyl 153 benzo C(R₄) bromo S ethoxy ethoxy CH₂4-trifluoro methylthio- phenyl 154 benzo C(R₄) bromo S ethoxy ethoxy CH₂4-trifluoro methyl- phenyl 155 benzo C(R₄) bromo S ethoxy ethoxy CH₂4-trifluoro methoxy- phenyl 156 benzo C(R₄) bromo S ethoxy ethoxy CH₂3-methoxy- 4-fluoro- phenyl 157 benzo C(R₄) bromo S isopropyl isopropylCH₂ 3-methoxy- oxy oxy 4-fluoro- phenyl 158 benzo C(R₄) bromo S ethoxyethoxy CH₂ 3-fluoro-4- methoxy- phenyl 159 benzo C(R₄) bromo S isopropylisopropyl CH₂ 3-fluoro-4- oxy oxy methoxy- phenyl 160 benzo C(R₄) bromoS ethoxy ethoxy CH₂ 2,3,5,6- tetrafluoro- 4-methoxy- phenyl 161 benzoC(R₄) bromo S isopropyl isopropyl CH₂ 2,3,5,6- oxy oxy tetrafluoro-4-methoxy- phenyl 162 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 2-fluoro-3-methoxy- phenyl 163 benzo C(R₄) bromo S isopropyl isopropyl CH₂2-fluoro-4- oxy oxy methoxy- phenyl 164 benzo C(R₄) bromo S ethoxyethoxy CH₂ 2-fluoro-4- chloro-5- methoxy- phenyl 165 benzo C(R₄) bromo Sisopropyl isopropyl CH₂ 2-fluoro-4- oxy oxy chloro-5- methoxy- phenyl166 benzo C(R₄) bromo S isopropyl isopropyl CH₂ 3-chloro- oxy oxy phenyl167 benzo C(R₄) chloro S isopropyl isopropyl CH₂ 3-trifluoro oxy oxymethyl-4- chloro- phenyl 168 benzo C(R₄) chloro S isopropyl isopropylCH₂ 2-fluoro-3- oxy oxy trifluoro methyl- phenyl 169 benzo C(R₄) chloroS isopropyl isopropyl CH₂ 3-fluoro-5- oxy oxy trifluoro methyl- phenyl170 benzo C(R₄) chloro S isopropyl isopropyl CH₂ 3-trifluoro oxy oxymethyl- phenyl 171 benzo C(R₄) chloro S isopropyl isopropyl CH₂ 3,5-di-oxy oxy trifluoro methyl- phenyl 172 benzo C(R₄) chloro S isopropylisopropyl CH₂ 2-fluoro-5- oxy oxy trifluoro methyl- phenyl 173 benzoC(R₄) chloro S isopropyl isopropyl CH₂ 2-trifluoro oxy oxy methyl-phenyl 174 benzo C(R₄) chloro S isopropyl isopropyl CH₂ 3-fluoro-4- oxyoxy trifluoro methyl- phenyl 175 benzo C(R₄) chloro S isopropylisopropyl CH₂ 4-trifluoro oxy oxy methyl- phenyl 176 benzo C(R₄) chloroS isopropyl isopropyl CH₂ 3-trifluoro oxy oxy methyl-4- methoxy- phenyl177 benzo C(R₄) chloro S isopropyl isopropyl CH₂ 2-chloro-3- oxy oxytrifluoro methyl- phenyl 178 benzo C(R₄) chloro S isopropyl isopropylCH₂ 2-chloro-5- oxy oxy trifluoro methyl- phenyl 179 benzo C(R₄) chloroS isopropyl isopropyl CH₂ phenyl oxy oxy 180 benzo C(R₄) chloro Sisopropyl isopropyl CH₂ 3-chloro- oxy oxy phenyl 181 benzo C(R₄) chloroS isopropyl isopropyl CH₂ 4-chloro- oxy oxy phenyl 182 benzo C(R₄)chloro S isopropyl isopropyl CH₂ 3-bromo- oxy oxy phenyl 183 benzo C(R₄)chloro S isopropyl isopropyl CH₂ 2,6-dichloro- oxy oxy phenyl 184 benzoC(R₄) chloro S isopropyl isopropyl CH₂ 3-chloro-4- oxy oxy trifluoromethoxy- phenyl 185 benzo C(R₄) chloro S isopropyl isopropyl CH₂2-fluoro-3- oxy oxy chloro- phenyl 186 benzo C(R₄) chloro S isopropylisopropyl CH₂ 3-chloro-5- oxy oxy fluoro- phenyl 187 benzo C(R₄) chloroS isopropyl isopropyl CH₂ 4-trifluoro oxy oxy methoxy- phenyl 188 benzoC(R₄) chloro S isopropyl isopropyl CH₂ 3-trifluoro oxy oxy methyl-4-fluoro- phenyl 189 benzo C(R₄) chloro S isopropyl isopropyl CH₂3-fluoro-4- oxy oxy chloro- phenyl 190 benzo C(R₄) bromo S isopropylisopropyl CH₂ 3-fluoro-4- oxy oxy chloro- phenyl 191 benzo C(R₄) chloroS isopropyl isopropyl CH₂ 2-fluoro-4- oxy oxy trifluoro methyl- phenyl192 benzo C(R₄) bromo S isopropyl isopropyl CH₂ 3-fluoro- oxy oxy phenyl193 benzo C(R₄) bromo S isopropyl isopropyl CH₂ 3,5-difluoro- oxy oxyphenyl 194 benzo C(R₄) bromo S isopropyl isopropyl CH₂ 2,3-difluoro- oxyoxy phenyl 195 benzo C(R₄) bromo S isopropyl isopropyl CH₂ 2-fluoro-3-oxy oxy chloro-5- trifluoro methyl- phenyl 196 benzo C(R₄) bromo Sisopropyl isopropyl CH₂ 2-fluoro- oxy oxy phenyl 197 benzo C(R₄) bromo Sisopropyl isopropyl CH₂ 4-fluoro- oxy oxy phenyl 198 4-bromo- C(R₄)bromo S isopropyl isopropyl CH₂ 2-fluoro- benzo oxy oxy phenyl 1996-bromo- C(R₄) bromo S isopropyl isopropyl CH₂ 2-fluoro- benzyl oxy oxyphenyl 200 6-bromo- C(R₄) bromo S isopropyl isopropyl CH₂ 4-fluoro-benzyl oxy oxy phenyl 201 benzo C(R₄) bromo S methoxy methoxy CH₂3,4-difluoro- phenyl 202 4-fluoro- C(R₄) methyl O isopropyl isopropylCH₂ 3,4-difluoro- benzo oxy oxy phenyl 203 benzo C(R₄) bromo S s-butyls-butyl CH₂ 3,4-difluoro- phenyl 204 benzo C(R₄) bromo S s-butyl s-butylOCH₂ 3,4-difluoro- phenyl 205 4-fluoro- C(R₄) bromo O isopropylisopropyl CH₂ 3,4-difluoro- benzo oxy oxy phenyl 206 4-fluoro- C(R₄)bromo O ethoxy ethoxy CH₂ 3,4-difluoro- benzo phenyl 207 (2,3-b) C(R₄)bromo S isopropyl isopropyl CH₂ 3,4-difluoro- pyridin-2- oxy oxy phenylyl 208 benzo C(R₄) thien-3-yl S ethoxy ethoxy CH₂ 3,4-difluoro- phenyl209 benzo C(R₄) bromo S n-butyloxy n-butyloxy CH₂ 3,4-difluoro- phenyl210 benzo C(R₄) bromo S 2-(2- 2-(2- CH₂ 3,4-difluoro- methoxy- methoxy-phenyl ethoxy)- ethoxy)- ethoxy ethoxy 211 benzo C(R₄) bromo S 3-methyl-3-methyl- CH₂ 3,4-difluoro- butoxy butoxy phenyl 212 benzo C(R₄) bromo Smethoxy methoxy CH₂ 3,4-difluoro- carbony- carbony- phenyl methoxymethoxy 213 benzo C(R₄) bromo S 2-acetoxy- 2-acetoxy- CH₂ 3,4-difluoro-ethoxy ethoxy phenyl 214 benzo C(R₄) phenyl S ethoxy ethoxy CH₂3,4-difluoro- phenyl 215 benzo C(R₄) 2-hydroxy- S ethoxy ethoxy CH₂3,4-difluoro- phenyl phenyl 216 benzo C(R₄) 2-fluoro- S ethoxy ethoxyCH₂ 3,4-difluoro- phenyl phenyl 217 benzo C(R₄) 3-fluoro- S ethoxyethoxy CH₂ 3,4-difluoro- phenyl phenyl 218 benzo C(R₄) 3-amino S ethoxyethoxy CH₂ 3,4-difluoro- carbonyl- phenyl phenyl 219 benzo C(R₄)3-methoxy S ethoxy ethoxy CH₂ 3,4-difluoro- carbonyl- phenyl phenyl 220benzo C(R₄) 4-fluoro- S ethoxy ethoxy CH₂ 3,4-difluoro- phenyl phenyl221 4-fluoro- C(R₄) bromo S isopropyl isopropyl CH₂ 3,4-difluoro- benzooxy oxy phenyl 222 4-fluoro- C(R₄) bromo S isopropyl isopropyl CH₂3-trifluoro benzo oxy oxy methyl-4- fluoro- phenyl 223 4-fluoro- C(R₄)bromo S ethoxy ethoxy CH₂ 3-trifluoro benzo methyl-4- fluoro- phenyl 2244-fluoro- C(R₄) bromo S ethoxy ethoxy CH₂ 3,4-difluoro- benzo phenyl 225benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3-hydroxy- 4-fluoro- phenyl 226benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3-fluoro-4- hydroxy- phenyl 227benzo C(R₄) bromo S isopropyl isopropyl CH₂ 3-fluoro-4- oxy oxy hydroxy-phenyl 228 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 2,3,5,6- tetrafluoro-4-hydroxy- phenyl 229 benzo C(R₄) bromo S isopropyl isopropyl CH₂2,3,5,6- oxy oxy tetrafluoro- 4-hydroxy- phenyl 230 benzo C(R₄) bromo Sisopropyl isopropyl CH₂ 2-fluoro-3- oxy oxy hydroxy- phenyl 231 benzoC(R₄) bromo S ethoxy ethoxy CH₂ 2-fluoro-4- chloro-5- hydroxy- phenyl232 benzo C(R₄) bromo S isopropyl isopropyl CH₂ 2-fluoro-4- oxy oxychloro-5- hydroxy- phenyl 233 benzo C(R₄) bromo S ethoxy ethoxy CH₂3-trifluoro methyl-4- hydroxy- phenyl Enant benzo C(R₄) bromo Sisopropyl isopropyl CH₂ 3,4-difluoro- .A oxy oxy phenyl 234 Enant benzoC(R₄) bromo S isopropyl isopropyl CH₂ 3,4-difluoro- .B oxy oxy phenyl235 Enant benzo C(R₄) bromo S ethoxy ethoxy CH₂ 4-trifluoro .A methoxy-236 phenyl Enant benzo C(R₄) bromo S ethoxy ethoxy CH₂ 4-trifluoro .Bmethoxy- 237 phenyl 238 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 4-fluoro-phenyl Enant benzo C(R₄) bromo S ethoxy ethoxy CH₂ 4-fluoro- .A phenyl239 Enant benzo C(R₄) bromo S ethoxy ethoxy CH₂ 4-fluoro- .B phenyl 240241 benzo C(R₄) bromo S isopropyl isopropyl CH₂ 3-trifluoro oxy oxymethyl-4- fluoro- phenyl Enant benzo C(R₄) bromo S isopropyl isopropylCH₂ 3-trifluoro .A oxy oxy methyl-4- 242 fluoro- phenyl Enant benzoC(R₄) bromo S isopropyl isopropyl CH₂ 3-trifluoro .B oxy oxy methyl-4-243 fluoro- phenyl 244 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3-chloro-4-fluoro- phenyl 245 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 2-trifluoromethyl-4- fluoro- phenyl 246 benzo C(R₄) bromo S ethoxy ethoxy CH₂3-trimethyl thio-phenyl 247 benzo C(R₄) bromo S ethoxy ethoxy CH₂4-methyl thio-phenyl 248 benzo C(R₄) bromo S isopropyl isopropyl CH₂3-chloro-4- oxy oxy fluoro- phenyl 249 benzo C(R₄) bromo S isopropylisopropyl CH₂ 2-trifluoro oxy oxy methyl-4- fluoro- phenyl 250 benzoC(R₄) bromo S isopropyl isopropyl CH₂ 3-trifluoro oxy oxy methylthio-phenyl 251 benzo C(R₄) bromo S isopropyl isopropyl CH₂ 4- oxy oxymethylthio- phenyl 252 benzo C(R₄) bromo S isopropyl isopropyl CH₂4-methyl oxy oxy sulfonyl- phenyl 253 benzo C(R₄) chloro S isopropylisopropyl CH₂ 3-chloro-4- oxy oxy fluoro- phenyl 254 benzo C(R₄) chloroS isopropyl isopropyl CH₂ 2- oxy oxy trifluoro- methyl-4-fluoro- phenyl255 benzo C(R₄) chloro S isopropyl isopropyl CH₂ 3-trifluoro oxy oxymethylthio- phenyl 256 benzo C(R₄) chloro S isopropyl isopropyl CH₂4-methyl oxy oxy thio-phenyl 257 benzo C(R₄) bromo S ethoxy ethoxy CH₂4-chloro- phenyl 258 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3-fluoro-4-chloro- phenyl 259 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3-chloro-5-fluoro- phenyl 260 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 2-trifluoromethyl- phenyl 261 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3,5-ditrifluoro- methyl-phenyl 262 benzo C(R₄) bromo S ethoxy ethoxy CH₂4-trifluoro methyl sulfonyl- phenyl 263 benzo C(R₄) bromo S isopropylisopropyl CH₂ 4-trifluoro oxy oxy methyl sulfonyl- phenyl 264 benzoC(R₄) chloro S isopropyl isopropyl CH₂ 4-trifluoro oxy oxy methylsulfonyl- phenyl 265 benzo C(R₄) H O ethoxy ethoxy CH₂ 3,4-difluoro-phenyl 266 benzo C(R₄) bromo O ethoxy ethoxy CH₂ 3,4-difluoro- phenyl267 benzo C(R₄) bromo S isopropyl isopropyl CH₂ 3-chloro-2- oxy oxyfluoro- phenyl 268 benzo C(R₄) bromo S isopropyl isopropyl CH₂2-chloro-3- oxy oxy trifluoro methyl- phenyl 269 benzo C(R₄) chloro Sethoxy ethoxy CH₂ 2-chloro- phenyl 270 benzo C(R₄) chloro S ethoxyethoxy CH₂ 3-trifluoro methoxy- phenyl 271 benzo C(R₄) chloro S ethoxyethoxy CH₂ 3-chloro-4- trifluoro methoxy- phenyl 272 benzo C(R₄) chloroS ethoxy ethoxy CH₂ 3-chloro-2- fluoro- phenyl 273 benzo C(R₄) chloro Sethoxy ethoxy CH₂ 3-fluoro-4- trifluoro methyl- phenyl 274 benzo C(R₄)chloro S ethoxy ethoxy CH₂ 2-chloro-5- trifluoro methyl- phenyl 275benzo C(R₄) chloro S ethoxy ethoxy CH₂ 3-bromo- phenyl 276 benzo C(R₄)chloro S ethoxy ethoxy CH₂ 3-chloro-5- fluoro- phenyl 277 benzo C(R₄)chloro S ethoxy ethoxy CH₂ 4-trifluoro methoxy- phenyl 278 benzo C(R₄)chloro S ethoxy ethoxy CH₂ 3-fluoro-5- trifluoro methyl- phenyl 279benzo C(R₄) chloro S ethoxy ethoxy CH₂ 2-trifluoro methyl- phenyl 280benzo C(R₄) chloro S ethoxy ethoxy CH₂ 2-chloro-3- trifluoro methyl-phenyl 281 benzo C(R₄) chloro S ethoxy ethoxy CH₂ 2-fluoro-3- trifluoromethyl- phenyl 282 benzo C(R₄) chloro S ethoxy ethoxy CH₂ 3,5-di-trifluoro methyl- phenyl 283 benzo C(R₄) chloro S ethoxy ethoxy CH₂4-trifluoro methylthio phenyl 284 benzo C(R₄) chloro S ethoxy ethoxy CH₂4-fluoro- phenyl 285 benzo C(R₄) chloro S ethoxy ethoxy CH₂ 4-trifluoromethyl- phenyl 286 benzo C(R₄) chloro S ethoxy ethoxy CH₂ 2-fluoro-5-trifluoro methyl- phenyl 287 benzo C(R₄) chloro S ethoxy ethoxy CH₂4-chloro-3- trifluoro methyl- phenyl 288 benzo C(R₄) bromo S isopropylisopropyl CH₂ 4-chloro- oxy oxy phenyl 289 benzo C(R₄) bromo S isopropylisopropyl CH₂ 2-fluoro-4- oxy oxy trifluoro methyl- phenyl 290 benzoC(R₄) chloro S ethoxy ethoxy CH₂ 3-chloro- phenyl 291 benzo C(R₄) chloroS ethoxy ethoxy CH₂ 2-fluoro-4- trifluoro methyl- phenyl 292 benzo C(R₄)chloro S ethoxy ethoxy CH₂ 4-methoxy- 3-trifluoro methyl- phenyl 293benzo C(R₄) chloro S ethoxy ethoxy CH₂ 4-chloro- phenyl 294 benzo C(R₄)chloro S ethoxy ethoxy CH₂ 4-fluoro-3- trifluoro methyl- phenyl 295benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3-bromo- phenyl 296 benzo C(R₄)chloro S ethoxy ethoxy CH₂ 3-trifluoro methylthio- phenyl 297 benzoC(R₄) chloro S ethoxy ethoxy CH₂ 3-chloro-4- fluoro- phenyl 298 benzoC(R₄) chloro S ethoxy ethoxy CH₂ 4-fluoro-3- trifluoro methyl- phenyl299 benzo C(R₄) chloro S ethoxy ethoxy CH₂ 4- methylthio- phenyl 300benzo C(R₄) chloro S ethoxy ethoxy CH₂ 4-trifluoro methyl sulfonyl-phenyl 301 benzo C(R₄) chloro S isopropyl isopropyl CH₂ 3-trifluoro oxyoxy methoxy- phenyl 302 benzo C(R₄) chloro S isopropyl isopropyl CH₂4-chloro-3- oxy oxy fluoro- phenyl 303 benzo C(R₄) chloro S isopropylisopropyl CH₂ 5-chloro-2- oxy oxy fluoro- phenyl 304 benzo C(R₄) chloroS isopropyl isopropyl CH₂ 4-trifluoro oxy oxy methylthio- phenyl 305benzo C(R₄) chloro S ethoxy ethoxy CH₂ 5-chloro-2- fluoro- phenyl 306benzo C(R₄) chloro S isopropyl isopropyl CH₂ 4-fluoro- oxy oxy phenyl307 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 5-chloro-2- fluoro- phenyl 308benzo C(R₄) bromo S isopropyl isopropyl CH₂ 5-chloro-2- oxy oxy fluoro-phenyl 309 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3-cyano- phenyl 310benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3-pyrrol-1-yl- phenyl 311 benzoC(R₄) bromo S ethoxy ethoxy CH₂ 4-difluoro methoxy- phenyl 312 benzoC(R₄) bromo S ethoxy ethoxy CH₂ 4-cyano- phenyl 313 benzo C(R₄) bromo Sethoxy ethoxy CH₂ 3-methoxy carbonyl- phenyl 314 benzo C(R₄) bromo Sethoxy ethoxy CH₂ 3-methoxy- phenyl 315 benzo C(R₄) bromo S ethoxyethoxy CH₂ 3-nitro- phenyl 316 benzo C(R₄) bromo S ethoxy ethoxy CH₂3-hydroxy phenyl 317 benzo C(R₄) chloro S isopropyl isopropyl CH₂3-methoxy- oxy oxy phenyl 318 benzo C(R₄) bromo S ethoxy ethoxy CH₂3-amino- phenyl 319 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3,5-dimethoxy- phenyl 320 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 2-methoxy-phenyl 321 benzo C(R₄) bromo S ethoxy ethoxy CH₂ 4-methoxy- phenyl 322benzo C(R₄) bromo S ethoxy ethoxy CH₂ 3,5- dihydroxy- phenyl 323 benzoC(R₄) bromo S ethoxy ethoxy CH₂ 2-hydroxy- phenyl 324 benzo C(R₄) bromoS ethoxy ethoxy CH₂ 4-hydroxy- phenyl 325 benzo C(R₄) bromo S isopropylisopropyl CH₂ 3-hydroxy- oxy oxy phenyl 326 benzo C(R₄) bromo Sisopropyl isopropyl CH₂ 4-methoxy- oxy oxy 3-trifluoro methyl- phenyl327 benzo C(R₄) bromo N(t-butoxy isopropyl isopropyl CH₂ 4-fluoro-carbonyl) oxy oxy 3-trifluoro methyl- phenyl 328 benzo C(R₄) bromoN(MeI) isopropyl isopropyl CH₂ 4-fluoro-3- oxy oxy trifluoro methyl-phenyl 329 3-trifluoro C(R₄) bromo N(n-propyl) isopropyl isopropyl CH₂4-fluoro-3- methyl-4- oxy oxy trifluoro fluoro- methyl- benzo phenyl 3303-trifluoro C(R₄) bromo N(methane isopropyl isopropyl CH₂ 4-fluoro-3-methyl-4- sulfonyl oxy oxy trifluoro fluoro- methyl- benzo phenyl 331benzo C(R₄) bromo N(methyl isopropyl isopropyl CH₂ 4-fluoro-3- carbonyl)oxy oxy trifluoro- methyl- phenyl 332 benzo C(R₄) bromo N(n-propylisopropyl isopropyl CH₂ 4-fluoro-3- sulfonyl) oxy oxy trifluoro methyl-phenyl 333 benzo C(R₄) H S isopropyl isopropyl CH 3,4-difluoro- oxy oxyphenyl 334 benzo C(R₄) bromo S isopropyl isopropyl CH 3,4-difluoro- oxyoxy phenyl 335 benzo C(R₄) bromo S isopropyl isopropyl CH₂ 2-fluoro-5-oxy oxy trifluoro methyl- phenyl 336 benzo C(R₄) bromo S isopropylisopropyl CH₂ 4-trifluoro oxy oxy methyl- phenyl

Using the methods described in the schemes and specific examples, andadaptations thereof, compounds of Formula (Ia), shown in Table 2, wereprepared.

TABLE 2 Formula (Ia)

Cpd A W R₄ X R₁ R₂ R₃ L B 79 benzo C(R₄) methyl S ethoxy ethoxy CH₃ CH₂3,4- difluoro- phenyl 93 benzo C(R₄) bromo S isopropyl isopropyl bromoCH₂ 3,4- oxy oxy difluoro- phenyl

Using the methods described in the schemes and specific examples, andadaptations thereof, compounds of Formula (Ib) wherein R₃ is H, shown inTable 3, were prepared.

TABLE 3 Formula (Ib)

Cpd A W R₄ X R₁ R₂ L B 86 benzo na H S ethoxy ethoxy CH₂ 2- fluoro-phenyl 97 5- na H S ethoxy ethoxy CH₂ 4- fluoro- fluoro- benzo phenyl108 5- na H N(phenyl) ethoxy ethoxy CH₂ 4- chloro- fluoro- benzo phenyl

BIOLOGICAL EXAMPLES Example 1 In Vitro Canine TRPM8 Functional Assay

The functional activity of compounds of Formula (I) was determined bymeasuring changes in intracellular calcium concentration using aCa²⁺-sensitive fluorescent dye. The changes in fluorescent signal weremonitored by a fluorescence plate reader, either a FLIPR™ (MolecularDevices) or FDSS (Hamamatsu). Increases in intracellular Ca²⁺concentration were readily detected upon activation with icilin.

HEK293 cells stably expressing canine TRPM8 were routinely grown asmonolayers in Dulbecco's minimum essential medium supplemented with 10%FBS, 1 mM L-glutamine, 100 units/mL penicillin, 100 ug/mL streptomycinand 400 μg/mL G418. Cells were maintained in 5% CO₂ at 37° C. At 24 hrsprior to assay, cells were seeded in clear-base poly-D-lysine coated384-well plates (BD Biosciences, NJ, USA) at a density of 5,000 cellsper well in culture medium and grown overnight in 5% CO₂ at 37° C. Onassay day, growth media was removed and cells were loaded with Calcium 3Dye (Molecular Devices) for 35 min at 37° C., under 5% CO₂ and then for25 min at room temperature and atmosphere. Subsequently, cells weretested for agonist-induced increases in intracellular Ca²⁺ levels usingFLIPR™ or FDSS. Cells were challenged with a compound of Formula (I) (atvarying concentrations) and intracellular Ca²⁺ was measured for 5 minprior to the addition of icilin to all wells to achieve a finalconcentration which produces approximately an 80% maximal response. EC₅₀or IC₅₀ values for compounds of the present invention were determinedfrom eight-point dose-response studies and represent the concentrationof compound required to elicit or inhibit 50% of the maximal response,respectively.

Maximal fluorescence intensity (FI) achieved upon addition of icilin wasexported from the FLIPR or FDSS software and further analyzed usingGraphPad Prism 3.02 (Graph Pad Software Inc., CA, U.S.A.). Basal FI wassubtracted prior to normalizing data to percent of maximal response.Curves were generated using the average of quadruplicate wells for eachdata point, were analyzed using nonlinear regression of either sigmoidaldose response or sigmoidal dose response (variable slope). Finally, theEC₅₀ and IC₅₀ values were calculated with the best-fit dose curvedetermined by GraphPad Prism. The resultant data are display in Table 4.

TABLE 4 TRPM8 Screening % I % I Cpd (10 (5 % I % I No. Conc μM) μM) (1μM) (0.5 μM) IC50 (μM) 1 1 100, 101 0.0020, 0.0013, 0.069 2 1 1000.0040, 0.0040 0.015, 0.015, 0.017 0.017 3 1 100 0.012, 0.051 4 1 1000.022 5 1 100 0.026 6 1 100 0.028 7 1 100 0.031 8 1 100 0.037 9 1 1000.041 10 1 100 0.043 11 1 99, 103 0.043, 0.047 12 1 100 0.043, 0.13 13 1100 0.046 14 1 100, 0.047, 0.080 101, 102 15 1 99, 100, 0.029, 0.048,103 0.105 16 1 100 0.057, 0.064 17 1 100 0.058 18 1 100 0.065 19 1 1000.068 20 1 100 0.070 21 1 100 0.088 22 1 100, 0.090, 0.101, 100 0.152 231 100 0.096 24 1 100 0.107 25 1 101 0.12, 0.19 26 1 100 0.108 27 1 990.110 28 1 100 0.110 29 1 100 0.116 30 1 100, 99 0.12, 0.20 31 1 1000.12 32 1 100 0.121 33 1 101 0.123 34 1 100, 0.12, 0.15, 101, 101 0.2035 1 100 0.125 36 1 100 0.126 37 1 100 0.127 38 1 99 0.14 39 1 100 0.14140 1 100 0.145 41 1 100 0.146 42 1 100, 0.15, 0.14 100 43 1 100 0.16 441 100, 0.16, 0.17 100 45 1 100 0.164 46 1 99 0.167 47 1 100 0.167 48 1100 0.169 49 1 100 0.171 50 1 99 0.184 51 5 101, 0.20, 0.30 101 52 1 990.22, 0.056 53 1 100, 97 0.22, 0.26 54 1 100 0.23 55 1 100 0.24 56 1 1030.24 57 1 100 0.26 58 1 100 0.27 59 1 99 0.27 60 1 100 0.28 61 1 1000.28 62 1 95 0.29 63 1 100 0.30 64 1 64 0.30 65 1 100 0.30 66 1 100 0.3367 1 100 0.33 68 1 96 0.34 69 1 99 0.35 70 1 & 5 99 82 0.35 71 1 98 0.3672 1 99 0.36 73 1 100 0.36 74 1 92 0.38 75 1 100 0.39 76 1 100 0.40 77 198 0.41 78 1 95 0.43 79 1 88 0.43 80 1 & 5 100 93 0.43 81 1 100, 870.44, 0.61 82 1 87 0.44 83 1 84 0.45 84 1 97 0.46 85 1 & 5 100 90 0.4886 5 101 0.50 87 1 93 0.50 88 1 80, 89 0.50, 0.54 89 1 & 5 100 91 0.5290 1 89 0.54 91 1 100 0.57, 0.16 92 1 91 0.58 93 1 80 0.58 94 1 & 5 9879 0.60 95 1 & 5 100 89 0.60 96 1 92 0.64 97 5 100 0.70 98 1 79 0.71 991 100 0.72 100 1 82 0.73 101 1 55 0.75 102 1 86 0.75 103 1 60 0.93 104 1& 5 99 53 0.96 105 1 & 5 100 48 1.01 106 1 32 1.26 107 5 99 1.30 108 586 1.40 109 1 & 5 98 17 1.47 110 1 & 5 96 11 2.32 111 1 14 — 112 1 42 —113 1 25 — 114 1 15 — 115 1 69 — 116 1 64 — 117 1 28 — 118 1 23 — 119 195 0.35 120 1 102 0.39 121 1 103 0.35 122 1 102 0.35 123 1 103 0.28 1241 103 0.049 125 1 103 0.39 126 1 100 0.41 127 1 100 0.052 128 1 1000.020 129 1 102 0.27 130 1 100 0.11 131 1 28 — 132 1 102 0.11 133 1 1010.34 134 1 101 0.34 Diast. A, 90 0.41 135 Diast. B, 91 0.42 136 137 0.5102 0.024 138 0.5 102 0.044 139 0.5 102 0.06 140 0.5 102 0.056 141 0.5100 0.051 142 0.5 101 0.054 143 0.5 101 0.067 144 0.5 101 0.058 145 0.5103, 0.119, 0.116 102 146 0.5 103 0.100 147 0.5 103 0.125 148 0.5 1030.172 149 0.5 103 0.060 150 0.5 103 0.090 151 0.5 103 0.120 152 0.5 102,92 0.054, 0.050 153 0.5 103 0.043 154 0.5 103 0.027 155 0.5 104, 0.046,0.12, 101, 102 0.09 156 0.5 103, 98 0.015, 0.032 157 0.5 103, 98 0.003,0.017 158 0.5 101 0.059 159 0.5 103 0.036 160 0.5 87 0.060 161 0.5 1030.019 162 0.5 103 0.032 163 0.5 103 0.020 164 0.5 94 0.082 165 0.5 1020.086 166 0.5 103 102 0.018, 0.014 167 0.5 104 0.097 168 0.5 104 0.076169 0.5 104 0.096 170 0.5 103 0.073 171 0.5 95 0.221 172 0.5 104 0.105173 0.5 103 0.140 174 0.5 104 0.089 175 0.5 104 0.072 176 0.5 104 0.131177 0.5 96 0.139 178 0.5 79 0.355 179 0.5 103 0.068 180 0.5 103 0.075181 0.5 103 0.112 182 0.5 104 0.075 183 0.5 103 0.131 184 0.5 104 0.057185 0.5 103 0.071 186 0.5 104 0.051 187 0.5 103 0.062 188 0.5 103 0.064189 0.5 103 0.122 190 0.5 104 0.102 191 0.5 104 0.125 192 0.5 103 0.038193 0.5 103 0.059 194 0.5 103 0.041 195 0.5 103 0.061 196 0.5 100 0.048197 0.5 100 102 0.045, 0.020 198 0.5 98 0.357 199 0.5 81 200 0.5 81 2010.5 100 0.133 202 0.5 103 0.053 203 0.5 96 0.457 204 0.5 100 0.092 2050.5 101 0.050 206 0.5 100 0.098 207 0.5 99 0.051 208 0.5 104 0.104 2090.5 104 0.071 210 0.5 62 211 0.5 97 0.095 212 0.5 102 0.119 213 0.5 1000.202 214 0.5 101 0.08 215 0.5 101 0.085 216 0.5 100 0.126 217 0.5 1000.142 218 0.5 79 0.483 219 0.5 68 220 0.5 101 0.207 221 0.5 102 0.032222 0.5 103 0.033 223 0.5 102 0.052 224 0.5 102 0.044 225 0.5 103 0.027226 0.5 34 227 0.5 52 228 0.5 94 0.129 229 0.5 95 0.156 230 0.5 97 0.01231 0.5 98 0.122 232 0.5 99 0.063 233 0.5 70 234 0.5 104 0.029 235 0.593, 56 0.253 236 0.5 103, 103 0.122, 0.099, 0.035, 0.124 237 0.5 96, 700.307, 0.338 0.147, 0.121 238 0.5 104 0.044 239 0.5 103, 103 0.037,0.027, 0.031 240 0.5 98, 77 0.225, 0.057 241 0.5 103 102 0.038 242 0.5103 0.009 243 0.5 80, 64 0.089 244 0.5 103 0.028 245 0.5 103 0.124 2460.5 104 0.102 247 0.5 103 0.121 248 0.5 104 0.021 249 0.5 103 0.054 2500.5 103 0.048 251 0.5 103 0.045 252 0.5 44 253 0.5 103 0.034 254 0.5 1030.079 255 0.5 103 0.058 256 0.5 103 0.056 257 0.5 101 0.026 258 0.5 1020.045 259 0.5 103 0.023 260 0.5 103 0.077, 0.056 261 0.5 102 0.073,0.077 262 0.5 103 0.066 263 0.5 103 0.022 264 0.5 103 0.029 265 1 950.409 266 1 103 0.051 267 1 101, 102 0.047, 0.029 268 0.5 104 0.034 2690.5 102 0.162 270 0.5 102 0.202 271 0.5 103 0.104 272 0.5 103 0.114 2730.5 103 0.116 274 0.5 95 0.301 275 0.5 103 0.104 276 0.5 103 0.114 2770.5 103 0.116 278 0.5 103 0.159 279 0.5 97 0.291 280 0.5 101 0.227 2810.5 102 0.131 282 0.5 100 0.235 283 0.5 103 0.125 284 0.5 103, 1020.079, 0.065 285 0.5 103 0.125 286 0.5 102 0.127 287 0.5 103 0.124 2880.5 103 0.065 289 0.5 103 0.051 290 0.5 103 0.115 291 0.5 103 0.156 2920.5 99 0.216 293 0.5 103 0.156 294 0.5 103 0.118 295 0.5 102, 103 0.031,0.016 296 0.5 102 0.137 297 0.5 103 0.040 298 0.5 99 0.085 299 0.5 1010.141 300 0.5 103 0.089 301 0.5 102 0.054 302 0.5 103 0.079 303 0.5 1020.049 304 0.5 102 0.028 305 0.5 102 0.070 306 0.5 101, 102 0.066, 0.031307 0.5 103 0.026 308 0.5 103 0.017 309 0.5 103 0.088 310 0.5 102 0.042311 0.5 102 0.053 312 0.5 102 0.089 313 0.5 102 0.083 314 0.5 103, 1040.029, 0.021 315 0.5 103 0.041 316 0.5 103, 104 0.032, 0.020 317 0.5 1020.021 318 0.5 100 0.211 319 0.5 103 0.026 320 0.5 103 0.028 321 0.5 1020.043 322 0.5 45 323 0.5 104 0.009 324 0.5 54 325 0.5 97 0.010 326 0.5103, 102 0.086, 0.051 327 0.5 44 328 0.5 102 0.193 329 0.5 100 0.177 3300.5 103 0.137 331 0.5 101 0.152 332 0.5 72 333 0.5 95 0.176 334 0.5 970.110 335 0.5 102 0.035 336 0.5 102 0.043

In Vivo Models Example 2 Inhibition of Icilin-Induced Behaviors inRodents

Icilin was initially developed as a “super-cooling” compound by DelmarChemicals Ltd. Subsequently it was shown to be one of the most potentknown agonists of TRPM8 (McKerny D D, et al. Nature 2002, 416(6876):52-8), having an EC₅₀=0.2 μM in stimulating calcium ion influx intoTRPM8 transfected cells (Behrendt H J et al. Brit J Pharmacol 2004,141(4): 737-45). Initial in vivo testing of icilin showed it to cause“wet-dog” shakes in rats. Similar shaking or jumping behavior was alsoevident in mice, rabbits, cats, dogs and monkeys. In humans, icilinproduced a sensation of coolness on contact with mucous membranes, coldprickling when 0.1 mg was dropped on the tongue and coldness in themouth, pharynx and chest lasting 30-60 minutes when 5-10 mg was ingestedorally (Wei E T, Seid D A, J Pharm Pharmacol. 1983, 35, 110). Theinhibition of icilin-induced shaking behaviors in rodents providesevidence for the utility of TRPM8 antagonists of Formula (I) inmodulating TRPM8-mediated effects in vivo.

Example 2a Inhibition of Icilin-Induced “Wet-Dog” Shakes in Rats

Male Sprague Dawley rats (275-500 g, Charles River Labs,n=4-6/treatment) were administered icilin in PEG-400 at 1.0 mg/kg, i.p.Spontaneous “wet-dog” shakes were counted in 2 minute bins over 30minutes post-icilin. Selected compounds of Formula (I) were administeredi.p. 15 minutes before icilin to assess their ability to inhibit(relative to vehicle pretreatment) this spontaneous “wet-dog” shake(WDS) phenomena. Percent inhibition was calculated as follows: %Inhibition=[1−(treatment WDS count/vehicle WDS count)]×100. Theresultant data are shown in Table 5.

TABLE 5 Dose ED50 Cpd (mg/kg) Route Pre icilin % Inhibition mg/kg 1 30i.p. 15′ 22.6 2 30 i.p. 15′ 88.9 14 30 i.p. 15′ 73.1 15 30 i.p. 15′ 71.134 30 i.p. 15′ 28.8 42 30 i.p. 15′ 70.6 53 30 i.p. 15′ 65.6 234 10 p.o.15′ 14.2 234 30 p.o. 15′ 68.0 234 100 p.o. 15′ 92.9 24.3

Example 2b Reversal of Icilin-Induced Behaviors in Rats

Compounds of Formula (I) capable of inhibiting the onset oficilin-induced “wet-dog” shaking behavior may be further assessed fortheir ability to reverse an existing icilin-induced “wet-dog” shakingbehavior. In this paradigm, icilin-induced shaking was counted for 10minutes followed by administration of a compound of Formula (I). Thediminution of shaking behavior is represented as a percent inhibitionrelative to icilin-induced shakes in the absence of test compoundadministration, as described by the following formula: %Inhibition=[1−(WDS count following test compound dose/WDS count prior totest compound dose)]×100. The resultant data are shown in Table 6.

TABLE 6 ED50 Cpd Dose (mg/kg) Route Post-icilin % Inhibition mg/kg 14 30i.p. 14′ 93.6 234 10 p.o. 1 h 24.4 234 30 p.o. 1 h 56.1 234 100 p.o. 1 h75.1 28.5 236 30 p.o. 1 h 36.8 239 30 p.o 1 h 48.4 242 30 p.o 1 h 79.9

Example 3 In Vivo Model for of Chronic Inflammatory Pain CompleteFreund's Adjuvant (CFA)-Induced Hyperalgesia

Intraplantar injection of Complete Freund's Adjuvant (CFA) in rodentsresults in a long-lasting inflammatory reaction, characterized by apronounced hypersensitivity to both thermal and mechanical stimuli. Thishypersensitivity peaks between 24-72 hours following injection and canlast for several weeks. To assess whether test compounds of Formula (I)reverse established hypersensitivity, a 100 μL intraplantar injection ofCFA (suspended in a 1:1 emulsion of saline and heat-killed Mycobacteriumtuberculosis in mineral oil) was injected into a single hind paw ofSprague-Dawley rats (typically males ranging from 150-350 g). Thisparadigm also may be conducted with a multiple dosing or a prophylacticdosing regime designed to alter the course of hyperalgesia development.This test predicts the analgesic, anti-allodynic and antihyperalgesiceffect of numerous effective clinical agents, including NSAIDS such asacetaminophen, aspirin and ibuprofen, and opioids such as morphine.

Example 3a CFA-Induced Paw Radiant Heat Hypersensitivity

Each rat was placed in a test chamber on a warm glass surface andallowed to acclimate for approximately 10 minutes. A radiant thermalstimulus (beam of light) was then focused through the glass onto theplantar surface of each hind paw in turn. The thermal stimulus wasautomatically shut off by a photoelectric relay when the paw was movedor when the cut-off time was reached (20 seconds for radiant heat at ˜5Amps). An initial (baseline) response latency to the thermal stimuluswas recorded for each animal prior to the injection of CFA. Twenty-fourhours following intraplantar CFA injection, the response latency of theanimal to the thermal stimulus was then re-evaluated and compared to theanimal's baseline response time. Only rats that exhibited at least a 25%reduction in response latency (i.e. hyperalgesia) were included infurther analysis. Immediately following the post-CFA latency assessment,test compound or vehicle (usually Solutol, hydroxypropylmethylcellulose, hydroxypropyl beta-cyclodextrin or PEG-400) wasadministered i.p. or p.o. to rats. Post-compound treatment withdrawallatencies were assessed at fixed time intervals, typically 30, 60 and120 minutes. The percent reversal (% R) of hypersenstivitiy wascalculated according to the following formula:% Reversal=(Treatment Response−CFA Response)/(Baseline Response−CFAResponse)×100.Resultant data are shown in Table 7.

TABLE 7 Dose % Cpd (mg/kg) Route Reversal Time ED₅₀ 2 30 i.p. 74 1 h 530 i.p. 38 30′ 12 30 i.p. 105 1 h 14 30 i.p. 40 30′, 1 h, 2 h 14 30 i.p.63 1 h 20.7 30 p.o. 47 2 h — 15 30 i.p. 95 1 h 30 p.o. 82 1 h 53 30 i.p.77 30′ 30 p.o. 44 2 h 127 30 p.o. 88 1 5.2 137 30 p.o. 34 1 155 30 p.o.138 1 190 30 p.o. 45 1 197 30 p.o. 23 2 234 30 p.o. 56 2 6.6 30 p.o. 751 235 30 p.o. 45 1 236 30 p.o. 25 2 238 30 p.o. 56 2 239 30 p.o. 36 2241 30 p.o. 72 1 244 30 p.o. 45 2 298 30 p.o. 20 1 299 30 p.o. 23 1 33530 p.o. 0 1 336 30 p.o. 64 1

A 3-point dose-response study in the CFA-induced Paw Radiant Heat model,using a 10% solutol vehicle, was obtained. A dose-dependent reversal ofhyperalgesia was observed, with an oral ED₅₀ of 11.4 mg/kg and 5.2 mg/kgfor Compounds 15 and 127, respectively, at the 1 h time point.

Example 3a CFA-Induced Paw Cold Hypersensitivity

Prior to intraplantar CFA injection mice were placed individually inelevated observation chambers having wire mesh floors. Through the meshfloor a series of three applications of acetone (0.04 mL/application)was sprayed onto the bottom of the paw using a multidose syringe device.A positive response took the form of an abrupt withdrawal and licking ofthe paw. The cumulative duration of licking was recorded for each of thethree trials which were then averaged to give the individual's response.Twenty-four hours following CFA injection acetone licking durations weremarkedly elevated implying a hypersensitivity to cooling. A testcompound of Formula (I) was assessed for its ability to returnacetone-evoked paw licking durations to pre-CFA levels (typically nearzero) following systemic administration. Percent inhibition wascalculated % Inhibition=[1−(treatment licking duration/vehicle lickingduration)]×100. The resultant data are displayed in

TABLE 8 Dose Cpd (mg/kg) Route % I Time 242 60 p.o. 84 30′

Example 4 Chemically-Induced Abdominal Irritant Models of Visceral Pain

A chemical irritant (such as acetic acid, kaolin, bradykinin,phenyl-p-(benzo) quinine, bromo-acetylcholine, or zymosan) is injectedin mice intraperitoneally, causing a contraction of the abdominalmusculature, which is characterized by an elongation of the bodyextending through to the hind limbs. The number of such responses isquantitated and is reduced by pretreatment of analgesic agents, thusforming the basis for a screening test (Collier H O et al. Br JPharmacol Chemother 1968, 32(2): 295-310). This type of abdominalirritant test has been used to predict the analgesic effect of numerousclinically effective agents, the potency of which in the abdominalirritant test parallels the magnitude of the dose needed in the reliefof clinical pain.

One modification of the chemically-induced abdominal irritant model ofvisceral pain is to pretreat animals with agents known to induceinflammatory responses following intraperitoneal injection (such as LPS,zymosan, or thioglycolate). A small intraperitoneal dose of such aninflammogen, administered hours or days before the acute chemicalirritant challenge, has been shown to increase the number of abdominalcontractions observed (Ribeiro R A, et al. Eur J Pharmacol 2000, 387(1):111-8). While some analgesic agents are effective at mitigating acuteviscerochemical nociception, others, particularly those dependent uponreceptor induction are more effective at preventing or reversing theenhancement of behavioral responses caused by a preconditioninginflammatory stimulus. Because of the up-regulation of the TRPM8receptor in inflammation, TRPM8 antagonists that are effective atreducing the mean number of contractions are predicted to provideantiinflammatory action in human clinical use.

The ability of compounds of Formula (I) to mitigate chemical irritantinduced abdominal contractions following a pre-conditioning inflammatorystimulus were studied. Thioglycolate (3%, w/v, 2-3 mL i.p.) was injectedinto male CD1 mice (20-40 g, Charles River Labs), at a maximum dosagevolume of 80 mL/kg, to induce peritoneal inflammation. Following atwenty-four hour pre-inflammation period these mice were dosed orallywith a compound of Formula (I) (30 mg/kg; n=10) or vehicle (HPMC with 2%Tween80; n=9) and then one hour later subjected to an abdominal irritantchallenge of acetic acid (1%, 10 mL/kg, i.p.). Immediately followinginjection of acetic acid, mice were placed individually in glass belljars (approximately 15 cm in diameter) for counting of abdominalcontractions over the next 15 minutes. The total number of abdominalcontractions was summed for each treatment group and employed in thefollowing formula to calculate Percent Inhibition (% I):% I=[1−(test compound contractions/vehicle contractions)]×100.The resultant data are displayed in Table 9.

TABLE 9 Acetic acid graded abdominal irritant test with a 24-hourthioglycolate pretreatment. Dose Cpd (mg/kg) Route % I Time 15 30 p.o.33 1 h

Example 5 In Vivo Models of Neuropathic Pain

The sciatic nerve is the major sensorimotor innervation of the (hind)leg and foot. Injury to the sciatic nerve or its constituent spinalnerves often results in pain-related behaviors. In rats and mice, tightligation of the L5 spinal nerve with silk suture, partial tight ligationof the sciatic nerve with silk suture or loose ligation of the sciaticnerve with chromic gut suture each result in behaviors reminiscent ofneuropathic pain in humans. These lesions (one per animal) wereperformed surgically in anesthetized rodents. Both the spinal nerve andsciatic nerve lesions result in allodynia, a painful response tonormally innocuous stimuli, and hyperalgesia, an exaggerated response tonormally noxious stimuli. It is important to note that both of thesepain-related behaviors were evoked by the testing procedures and thatnormal use of the paw (e.g., walking) was relatively uncompromised,apart from occasional “guarding” of the paw. Subsequent to the surgery,the subjects' behaviors, such as grooming, feeding, and weight gain,were normal, except for hypersensitivity (as defined above) of theaffected paw.

In addition to induction by nerve damage resulting from accidentaltrauma or surgical procedures, neuropathic pain can also be induced bydiabetes (Fox, A et al., Pain 81:307-316, 1999) or by treatment withchemotherapeutic agents, such as paclitaxel or vincristine (Yaksh, T Let al., Pain 93:69-76, 2001).

Agents that attenuate neuropathic pain in the clinic also are effectivein rodent neuropathic pain models. These agents include the recentlyapproved Cymbalta (Duloxetine, Iyengar, S., et al., JPET 2004311:576-584), morphine (Suzuki, R et al., Pain 1999 80:215-228) andgabapentin (Hunter, J C et al., Eur J. Pharmacol. 1997 324:153-160). Thedual TRPV1/TRPM8 receptor antagonist BCTC reduced mechanicalhyperalgesia and tactile allodynia in the chronic constriction injuryrodent neuropathic pain model (Pomonis, J D et al., JPET. 2003306:387-393; Behrendt, H et al., Brit J. Pharm. 2004 141:737). Coldallodynia is a particularly debilitating symptom of neuropathic painconditions (Jorum E et al. Pain. 2003 101: 229-235).

Example 5a Chronic Constriction Injury (CCI)-Induced Model ofNeuropathic Pain Acetone-Induced Hypersensitivity

In male SD rats (175-325 g), four loose ligatures of 4-0 chromic gutwere surgically placed around the left sciatic nerve under inhalationanesthesia as described by Bennet et al (Bennett G J, Xie Y K. Pain1988, 33(1): 87-107). Seven to 21 days following sciatic chronicconstriction injury (CCI) surgery, the subjects were placed in elevatedobservation chambers having wire mesh floors. Through the mesh floor aseries of five applications of acetone (0.05 mL/application) was sprayedonto the bottom of the paw using a multidose syringe device. A positiveresponse took the form of an abrupt withdrawal or lifting of the paw.The percentage of positive responses from the five trials representedthe individual's overall response that was then averaged over the entiretreatment group. A test compound of Formula (I) was assessed for itsability to return acetone response frequencies to pre-lesion levels(typically zero) following systemic administration. An ascending doseresponse relationship (as in Table 10 below) was generated by additionof successive doses of test compound followed by re-assessment ofbehavior. The number of positive responses following administration oftest compound was taken as a percentage of the number of positiveresponses prior to test compound treatment. The resultant data aredisplayed in Table 10.

TABLE 10 Dose % of Allodynic ED50 Cpd No. (mg/kg) Route preR x Baseline(mg/kg) 14 10 47.7 30 31.8 100 s.c. 20′ 40.9 234 3 p.o. 1 hr 16.7 1051.7 30 59.6 100 83.1 3 p.o. 2 hr 10.0 30 56.7 100 93.3 p.o. 1 hr 14.8235 30 p.o. 1 hr 34.3 236 30 p.o. 4 hr 28.6 100 68.8 239 30 p.o. 1 hr29.4 242 30 i.p. 2 hr 63.3 3 p.o. 3 hr 15.0 10 30.0 30 66.7 100 86.7p.o. 3 hr 18.0

Example 5b Chronic Constriction Injury (CCI)-Induced Model ofNeuropathic Pain—Cold Plate-Induced Hypersensitivity

In male SD rats (175-325 g), four loose ligatures of 4-0 chromic gutwere surgically placed around the left sciatic nerve under inhalationanesthesia as described by Bennet et al (Bennett G J, Xie Y K. Pain1988, 33(1): 87-107). Seven to 21 days following sciatic chronicconstriction injury (CCI) surgery, the subjects were placed onto acommercial cold plate device cooled by peltier elements such that thesurface temperature was held at 1° C. Each subject underwent a 6 minuteconditioning period followed by a 3 minute assessment period duringwhich the total duration of hind paw lifting was recorded. Thisprocedure was repeated at several intervals prior to and followingsystemic drug administration. Test compounds of Formula (I) wereassessed for their ability to return duration of paw lifting back topre-lesion levels. The duration of paw lifting during the 3 minute testperiod following administration of test compound was taken as apercentage of the duration of paw lifting during the 3 minute testperiod prior to test compound treatment. The resultant data aredisplayed in Table 11.

TABLE 11 % of Dose Post Allodynic Cpd (mg/kg) Route dose Baseline 14 30i.p. 60′ 79.6 p.o. 60′ 68.5 p.o. 120′  61.8

Example 6 Inflammatory Agent-Induced Models of Pyresis/Antipyresis

Compounds of Formula (I) can be tested in animal models of pyresis,according to previously documented and validated methods, such as thosedescribed by Kozak et al (Kozak W, Fraifeld V. Front Biosci 2004, 9:3339-55). Fever is a frequent accompaniment of inflammatory disease.Animal models make use of the pyretic properties of yeast and otherinflammatory agents, injecting a yeast suspension or other agentsubcutaneously (Tomazetti J et al. J Neurosci Methods 2005, 147(1):29-35); Van Miert A S, Van Duin C T. Eur J Pharmacol 1977, 44(3):197-204). For example, Male Wistar rats (75-100 g) can be housed ingroups of four to a cage at controlled temperature (23±1° C.) with a 12h light:12 h dark cycle (lights on at 07:00 h) and with standard labchow and tap water ad libitum. All measured temperatures can be takenbetween 08:00 and 19:00 h. Each animal can be used in only one study.Rectal temperature (TR) can be measured by inserting a lubricatedthermistor probe (external diameter: 3 mm) 2.8 cm into the rectum of theanimal. The probe can be linked to a digital device, which displayed thetemperature at the tip of the probe with a 0.1° C. precision and logsthe values over time. Immediately after measuring the initial basalrectal temperature, the animals can be injected with commerciallyavailable dried baker yeast (Saccharomyces cerevisiae) suspended inpyrogen-free 0.9% NaCl (0.05-0.25 g/kg, i.p.) or 0.9% NaCl (10 ml/kg).TR changes can be recorded every hour up to 12 h, and expressed as thedifference from the basal value. Since it has been previously reportedthat handling and temperature measuring-related stress alter rectaltemperature, these animals can be habituated to the injection andmeasuring procedure for 2 days before experiments are carried out. Inthese sessions, the animals can be subjected to the same temperaturemeasuring procedure described above, and can be injectedintraperitoneally (i.p.) with 0.9% NaCl (10 ml/kg).

To assess the effect of potential antipyretic compounds on basal rectaltemperature study animals can have their TR measured for 4 h, and afterthe fourth TR measurement they can be subcutaneously (s.c.) injectedwith vehicle (such as 10% Solutol in sterile water 5 ml/kg) or acompound of Formula (I) prepared in vehicle. TR can then be recordedevery hour up to 8 h after the compound injections. To assess the effectof a compound of Formula (I) on baker yeast-induced hyperthermia, studyanimals can have their basal TR measured and then be injected with apyrogenic dose of baker yeast (for example, 0.135 g/kg). TR changes canbe recorded every hour up to 4 h, when potential antipyretics agentssuch as those of Formula (I) are administered. Rectal temperature canthen be monitored over the following 8 h. Basal rectal temperature andchanges in rectal temperature can be expressed as means±S.E.M. of thedifferences from TR at 07:00 h. Data can be analyzed by two-way analysisof variance (ANOVA), with time of measures treated as within subjectfactor, depending on the experimental design. Post hoc analysis can becarried out by the F-test for simple effect and the Student-Newman-Keulstest, when appropriate. A value of P<0.05 would be consideredstatistically significant.

The modification of the subsequent pyretic response by therapeuticagents can also be monitored by rectal telemetry or other measurementsof body temperature. Several clinically relevant agents such asacetaminophen, aspirin and ibuprofen, reduce fever in these models.

Example 7 CFA-Induced Model of Rheumatoid Arthritis

Compounds of Formula (I) can be tested in animal models of rheumatoidarthritis, according to previously documented and validated methods,such as those described by Nagakura et al (Nagakura Y, et al. JPharmacol Exp Ther 2003, 306(2): 490-7). For example, arthritis can beinduced by the CFA inoculation in the rats (Male Lewis rats 150-225 g;Charles River). Briefly, 100 mg of Mycobacterium butyricum (Difco,Detroit, Mich.) can be thoroughly mixed with 20 mL of paraffin oil. Thenmixture can be autoclaved for 20 min at 120° C. Each rat can be injectedin the right footpad (hind paw) with the mixture in a 0.1-mL volumeunder inhalation anesthesia. The rats serving as controls can beinjected with 0.1 mL of saline. Pain and other disease developmentparameters can be measured in the CFA- or saline-treated rats justbefore inoculation and up to 28 days post-inoculation. The measurementfor pain parameters can be conducted for both mechanical and thermal(hot or cold) endpoints. The measurement of mechanical allodynia can beperformed using the von Frey hairs (Semmes-Weinstein Monofilaments,Stoelting Co., IL) wherein the rats can be habituated to wire meshbottom cages before the start of the experiment. Static allodynia can betested in the unrestrained rats by touching the plantar surface of thehind paw with von Frey hairs in ascending order of force (1.2, 1.5, 2.0,3.6, 5.5, 8.5, 12, 15, 29, and 76 g) for up to 6 s or until a pawwithdrawal response can be elicited. The lowest amount of force requiredto elicit a response can be recorded as the withdrawal threshold in logg. Thermal hyperalgesia can be assessed using the radiant heat testwherein a mobile radiant heat source can be located under a glasssurface upon which the rat is placed. The beam of light can be focusedon the hind paw, and the paw withdrawal latencies are defined as thetime taken by the rat to remove its hind paw from the heat source. Themeasurement of joint hyperalgesia can be performed by a modification ofthe previously reported method (Rupniak N M J et al. Pain. 1997,71:89-97). The torso of each rat can be held from the back with the leftpalm, and the bending and extension (one after the other and five timesin each direction) of the ankle within its limits of range of motion canbe performed with the right fingers. The total number of vocalizationsemitted after the manipulation (the bending and extension, five times ineach direction) can be recorded for each paw (the maximum score is 10for each paw).

The scoring of mobility can be performed by modifying the evaluationscale reported by Butler et al. (Butler S H et al 1992 Pain 48:73-81):score 6, walks normally; score 5, walks being protective toward theipsilateral hind paw (touches the ipsilateral hind paw fully on thefloor); score 4, walks being protective toward the ipsilateral hind paw(touches only the toe of the ipsilateral hind paw on the floor); score3, walks being protective toward both hind paws (touches thecontralateral hind paw fully on the floor); score 2, walks beingprotective toward both hind paws (touches only the toe of thecontralateral hind paw on the floor); score 1, crawls only using thefore paws; and score 0, does not move. Paw volumes can be measured byvolume displacement of electrolyte solution in a commercially availableplethysmometer device. The hind paw can be immersed to the junction ofthe hairy skin, and the volumes can be read on a digital display. Thescoring of joint stiffness can be performed as follows: the body of ratscan be held from the back with the left palm, and the bending andextension (once in each direction) of the ankle within its limits ofrange of motion can be performed with the right fingers. It can beconfirmed beforehand that there is no restriction of ankle jointmovement in the bending and extension manipulations in naive rats, andthe scoring can be performed according to the evaluation scale reportedby Butler et al. (1992): score 2, there are restrictions of full rangeof movement of the ankle in both bending and extension; score 1, thereis a restriction of full range of movement of the ankle in bending orextension; and score 0, no restriction. The measurements for paw volumeand joint stiffness can be conducted for both hind paws.

Compounds of Formula (I) can be assessed for antihyperalgesic efficacyas follows: thirty-two rats (eight rats per dose and four doses percompound) that are be treated with the CFA and another eight rats asnaive controls can be used for each drug evaluation. The analgesiceffects can be evaluated on post-inoculation day 9, when mechanicalallodynia, thermal hyperalgesia, joint hyperalgesia, and joint stiffnessin the ipsilateral paw reached almost the maximum, although thoseparameters in the contralateral paw changed only slightly and thesystemic disturbance shown by the change of mobility score is small. Onthe day before evaluation, body weight, mechanical allodynia, thermalhyperalgesia, and joint hyperalgesia can be measured for the 32 ratsthat are to be used for compound evaluation. The rats are allocated tofour groups (eight rats per group) such that the differences in theaverages of those parameters among the groups became small. All theanalgesic effect evaluations and behavioral observations can be carriedout by the observer who is blind to the drug treatment.

Data can be expressed as the mean+/−S.E.M. The time-course curves formechanical allodynia, thermal hyperalgesia, joint hyperalgesia, bodyweight, and paw volume can be subjected to two-way repeated measuresanalysis of variance with post hoc t test. In experiments for evaluationof a compound of Formula (I), the difference in scores between thevehicle-treated and naive control groups can be analyzed by Student's ttest to confirm significant changes in the pain parameters in theipsilateral paw. The analgesic effects can be analyzed by Dunnett's ttest, and in each case the drug-treated groups can be compared with thevehicle-treated group. In each statistical analysis, the comparison canbe conducted for paws on the corresponding side. P<0.05 is consideredstatistically significant.

Example 8 In Vivo Model for Arthritis Inflammogen-Induced Hyperalgesiaof the Knee Joint

Compounds of Formula (I) can be tested in animal models ofosteoarthritis, according to previously documented and validatedmethods, such as those described by Sluka et al (Sluka K A, Westlund KN. Pain 1993, 55(3): 367-77). For example, male Sprague-Dawley rats(Harlan, Indianapolis, Ind.) weighing 225 to 350 g can be brieflyanesthetized with vaporized halothane and then injected with a mixtureof 3% carrageenan and 3% kaolin (100 μL in 0.9% sterile saline) into thejoint cavity of one knee. After the injection, the animals can bereturned to their cages until the time of testing. For behavioraltesting animals can be placed in individual clear plastic cages on topof an elevated wire mesh surface that restricted movement. The animalsshould be allowed to acclimate for approximately 1 hour before testing.Von Frey filaments, as described above, can then be used to test forenhanced responses to mechanical stimuli. The filaments can besuccessively applied through the wire mesh perpendicularly to theplantar surface in between the pads of the third and fourth phalanges.The response threshold to mechanical stimuli can be determined beforeinflammation of the knee joint; 4 hours after inflammation to confirmthe development of hyperalgesia; immediately after the administration oftest compound such as those of Formula (I) i.e. 5 hours afterinflammation; and at 8, 12, and 24 hours after inflammation.

The Kruskal-Wallis test, a nonparametric test, can be used to analyzethe effects for frequency, intensity, and group for response tomechanical stimuli at baseline, 4 hours after inflammation, and aftercompound treatment (5 hours, 8 hours, 12 hours, and 24 hours afterinflammation). Further post hoc testing between groups can be executedby using the Mann-Whitney signed rank test. The data can be presented asmedian with 25th and 75th percentiles. Significance is P≦0.05.

Additionally, the gait of the animal or other pain-related behavior canbe scored as the dependent measure of the painful effect of thearthritis on the animal's activity (Hallas B, Lehman S, Bosak A, et al.J Am Osteopath Assoc 1997, 97(4): 207-14). The effect of test drug onthe animal's normal behavior can be quantified from zero, meaning noresponse, to three for incapacitating impairment. Effective analgesictreatment includes the clinically used indomethacin (Motta A F, et al.Life Sci 2003, 73(15): 1995-2004).

Example 9 Sarcoma Cell-Induced Models of Bone Cancer Pain

Compounds of Formula (I) can be tested in animal models of bone cancerpain, according to previously documented and validated methods, such asthose described in the scientific literature (El Mouedden M, Meert T F.Pharmacol Biochem Behav 2005, 82(1): 109-19; Ghilardi J R, et al. JNeurosci 2005, 25(12): 3126-31). In preparation for cell inoculation andtumor induction, osteolytic murine sarcoma cells (NCTC 2472, AmericanType Culture Collection (ATCC), Rockville, Md., USA) can be cultured inNCTC 135 medium (Invitrogen) containing 10% horse serum (Gibco) andpassaged 2 times weekly according to ATCC guidelines. For theiradministration, cells can be detached by scraping and then centrifugedat 1000×g. The pellet can be suspended in fresh NCTC 135 medium (2.5×10⁶cells/20 μL) and then used for intramedullary femur inoculation. MaleC3H/HeNCrl mice (25-30 g, Charles River Labs) can be used in suchexperiments. After induction of general anesthesia with xylazine (10mg/kg i.p.) and ketamine (100 mg/kg i.p.) the left hind paw can beshaved and disinfected with povidone-iodine followed by 70% ethanol. Asuperficial incision of 1 cm can then be made over the knee overlayingthe patella. The patellar ligament can then be cut, exposing thecondyles of the distal femur. A 23-gauge needle can be inserted at thelevel of the intercondylar notch and the intramedullary canal of thefemur to create a cavity for injection of the cells. Twenty microlitersof media (sham animals) or media containing tumor cells (approximately2.5×10⁶ cells) can then be injected into the bone cavity using asyringe. To prevent leakage of cells outside the bone, the injectionsite can be sealed with dental acrylic and the wound closed with skinstitches.

Pain behaviors can be evaluated in separate groups (n=6) of sham andbone tumor mice with confirmed hyperalgesia as assessed by spontaneouslifting behavior. Animals can be behaviorally tested during a 3-weekperiod prior to and after tumor inoculation. Body weight of the mice canbe recorded throughout the experimental period to help monitor generalhealth status. To measure the spontaneous lifting, the animals can behabituated in a transparent acrylic cylinder of 20 cm diameter put on anhorizontal surface and thereafter observed during 4 min for spontaneouslifting behavior of the left hind paw. After spontaneous liftingbehavior assessment, animals can be immediately placed on a mouserotarod (e.g. ENV-575M\, Med Associates Inc., GA, USA) at a speed of 16rpm for 2 min wherein limb-use during forced ambulation is scored:4=normal; 3=limping; 2=partial non-use of left hind paw; 1=substantialnon-use of left hind paw; 0=nonuse of left hind paw. Assessment of coldallodynia may be made by exposing the ipsilateral hind paw of the mouseto 5 repeated applications of acetone (20 μL) and quantifying thelift/licking frequency and/or duration. Post-mortem evaluation of bonedestruction can be assessed by ACT processing followed by scanning usinga system such as the Skyscan 1076 microtomograph system for small animalimaging (Skyscan 1076\, Skyscan, Aartselaar, Belgium). Measuredhistomorphometry parameters of bone destruction can be subsequentlycorrelated with behavioral endpoints.

The antihyperalgesic, antiallodynic and disease modifying effects ofcompounds such as those of Formula (I) can be tested in this murinemodel of bone cancer pain in separate groups (n=6 per dose group).Animals with confirmed hyperalgesia, as assessed by spontaneous oracetone-evoked lifting, can be behaviorally tested, for example, on days15 and 22 after distal femur tumor inoculation before and 1 h aftersystemic administration of vehicle (e.g. 10% Solutol in sterile water)or a compound of Formula (I). The statistical analysis can be performedby one-way ANOVA to compare behavioral measurements and bone parametersamong the experimental groups. To compare behavioral measurements andbone parameters between sham and tumor-bearing animals, a Mann-Whitney Utest can be used. Results are considered statistically significant atP<0.05 (two-tailed). Data are expressed as mean+/−S.E.M.

Bone cancer causes intense pain in humans, mimicked in animal models ofbone cancer pain in rodents such as that described above. Analgesictreatments that are effective in this model include COX-2 inhibitors(Sabino M A, Ghilardi J R, Jongen J L, et al. Cancer Res 2002, 62(24):7343-9) and high doses of morphine (Luger N M et al. Pain. 2002, 99(3):397-406), agents used clinically for pain relief in patientsexperiencing bone cancer pain.

Example 10 Respiratory Irritant-Induced Models of Cough

Compounds of Formula (I) can be tested in animal models of antitussiveactivity, according to previously documented and validated methods, suchas those described by: Tanaka, M. and Maruyama, K. J. Pharmacol. Sci.2005, 99(1), 77-82; Trevisani, M. et al., Throax 2004, 59(9), 769-72;and Hall, E. et al., J. Med. Microbiol. 1999, 48: 95-98. Testing isconducted in transparent ventilated chambers with a constant airflow of400 mL/min. The tussive agent (citric acid 0.25 M or capsaicin 30 mM)can be nebulised via a miniultrasonic nebuliser with an output of 0.4mL/min. The appearance of cough can be detected by means of a tie clipmicrophone and confirmed by the characteristic posture of the animal.The cough sounds can be recorded and digitally stored. A blindedobserver subsequently counts the number of elicited cough efforts. Insome cases, animals can be sensitized by pre-exposure to certain agentssuch as ovalbumin. A test compound can be administered to at the peak ofirritant-induced cough to evaluate the antitussive effects of thecompound. In addition, prophylactic or multiple dosing regimes can beutilized to evaluate the test compound for modulation of the onset andduration of irritant-induced cough. Variations of these tests predictthe antitussive effects of effective clinical agents, including NMDAantagonists such as dextrorphan and dextromethorphan, opioids such ascodeine, beta 2 agonists such as salbutamol and antimuscarinics such asipratropium (Bolser, D. C. et al., Eur. J. Pharmacol. 1995, 277(2-3),159-64; Braga, P. C. Drugs Exper. Clin. Res. 1994, 20, 199-203).

Example 11 Chemical Irritant-Induced Models of Itch, Contact Dermatitis,Eczema and other Manifestations of Dermal Allergy, Hypersensitivityand/or Inflammation

Compounds of Formula (I) can be tested in animal models of contactdermatitis or itch, according to previously documented and validatedmethods, such as those described in the scientific literature(Saint-Mezard P et al. Eur J. Dermatol. 2004, 14(5): 284-95; Thomsen J.S., et al. J. Exp Dermatol. 2002, 11(4): 370-5; Weisshaar E, et al. ArchDermatol Res 1998, 290(6): 306-11; Wille J J, et al. Skin Pharmacol ApplSkin Physiol. 1999, 12(1-2): 18-27). Mice (or species such as guinea pigor rat) can be sensitized with 25 mL of 0.5% dinitrofluorobenzenesolution (DNFB diluted 4:1 in acetone:olive oil immediately beforeapplication or other haptens, such as 12-myristate-13 acetate, picrylchloride, oxazolone, capsaicin, arachidonic acid, lactic acid,trans-retinoic acid or sodium lauryl sulfate) painted to the shaveddorsal skin or untreated (controls). Five days later, 10 mL of 0.2% DNFBa nonirritant dose) can be applied onto both sides of the right ear andthe same amount of solvent alone onto the left ear. Ear thickness can bemonitored daily using a caliper. Compounds of Formula (I) can beadministered at the peak of inflammation to evaluate the anti-allergyactivity of compounds. In addition, prophylactic or multiple dosingregimes can be utilized to evaluate the test compound for modulation ofthe onset and duration of anti-allergy activity. Variations of thesetests can predict the anti-allergy and itch activity of effectiveclinical agents. The ability of these models to predict the therapeuticeffect of compounds in human dermal conditions is supported by thecross-species ability of serotonin to induce itch (Weisshaar E, GollnickH. Skin Therapy Lett 2000, 5(5): 1-2, 5). Additionally, for the contactsensitizing property of commercially important drugs and the ability ofion channel modulators to prevent and treat skin sensitization in thesemodels, see Kydonieus A, et al., Proceedings of the InternationalSymposium on Controlled Release of Bioactive Materials 24th:23-24, 1997.

Example 12 Chemical Irritant-Induced Models of Rhinitis and OtherManifestations of Nasal Hypersensitivity and/or Inflammation

Compounds of Formula (I) can be tested in animal models of rhinitis,according to previously documented and validated methods, such as thosedescribed in the scientific literature (Hirayama Y, et al. Eur J.Pharmacol. 2003, 467(1-3): 197-203; Magyar T, et al. Vaccine 2002,20(13-14): 1797-802; Tiniakov R L, et al. J Appl Physiol 2003, 94(5):1821-8). Testing can be conducted in mouse, guinea pig, dog or human inresponse to intranasal challenge with one or more irritants such as coldair, capsaicin, bradykinin, histamine, pollens, dextran sulfate,2,4-tolylene diisocyanate, Bordetella bronchiseptica, Pasteurellamultodica or acetic acid. In some cases, animals can be sensitized bypre-exposure to certain agents including, but not limited to, ragweed orovalbumin. Prior to or following irritant administration, the testsubject can receive, respectively, the prophylactic or therapeuticadministration one or more times of a compound of Formula (I), orvehicle control, by the enteral or parenteral route. Significantdifferences indicative of nasal rhinitis or sensitization for the testcompound-treated subjects compared with vehicle-treated subjects can betaken as evidence of anti-rhinitis activity. Independent variablesinclude dose, frequency and route of administration, time intervalbetween prophylactic or therapeutic test compound administration andirritant challenge as well as sex and non-sex genotype of the testsubject.

Example 13 Conflict-Induced Models of Anxiety, Panic Disorder and OtherNon-Adaptive Stressful or Phobic Responses

Compounds of Formula (I) can be tested in animal models of anxiety,panic disorders and other non-adaptive responses, according topreviously documented and validated methods, such as those described byCryan and Holmes (Cryan J F, Holmes A. Nat Rev Drug Discov 2005, 4(9):775-90) or Braw et. al. (Y. Braw et al. Behavioural Brain Research 2006,167: 261-269). Specifically, for studies in rats, the following apparatimay be utilized: an open-field arena (62 cm×62 cm) enclosed by opaquewalls (30 cm high) and plus-maze consists of two open arms, 50 cm×10 cm,and two enclosed arms, 50 cm×10 cm×40 cm with an open roof, arrangedsuch that the two arms of each type are opposite each other. The maze iselevated to a height of 70 cm. The walls of the enclosed arms are madefrom black Plexiglas, while the floors from white Plexiglas. Videotaperecordings can be analyzed using the ‘Observer’ system (NoldusInformation Technology). A subject rat can be removed from its homecage, weighed and placed gently in the center of the open-field arena.The rat can be allowed to explore the open-field freely while itsbehavior is videotaped for 5 min. Afterwards, it can be transferred tothe plus-maze and placed at the center, facing a closed arm. The rat'sbehavior can again be videotaped for 5 min, after which it can bereturned to its home cage. The apparatus can cleaned using a 70% ethanolsolution between rats.

Open-field and plus-maze measures can be grouped into two behavioralclasses, namely ‘anxiety-like behaviors’ and ‘activity’. Open-fieldbehavioral measures may include 1) Anxiety measures: % time in centersquare, % number of entries to center square (from total squaresentered), % time freezing, latency to first freezing (freezing is scoredwhen the subject is in an immobile state for at least 3 seconds; and 2)Activity measures: Total squares entered, number of rearings (standingon two hind legs), latency for first rearing. Plus-maze measures mayinclude 1) Anxiety: % time in open arms, % number of entries to openarms (from total entries), number of unprotected head dips, latency toenter open arm; and 2) Activity: Total entries to all arms. Anxiety-likebehaviors and activity can be analyzed by one-way ANOVA's on each of themeasures, for each the between-subject comparisons. Plus-maze analysescan be conducted in a similar fashion.

Testing may also be conducted in mouse or rat in this fashion in orderto measure avoidance of other aversive environmental stimuli such asGeller or Vogel anticonflict tests, the light/dark test and thehole-board test (see Cryan J F, Holmes A. Nat Rev Drug Discov 2005,4(9): 775-90). Prior to environmental exposure, the test subject canreceive the prophylactic administration one or more times of a compoundof Formula (I), or vehicle control (e.g. 10% Solutol in sterile water),by the enteral or parenteral route. The cumulative time or number oftimes spent engaged in the aversive behavior can be measured.Significant differences in one or more of these measures for the testcompound-treated subjects compared with vehicle-treated subjects can betaken as evidence of anxiolytic activity. These models arepharmacologically validated by the effectiveness of clinically usefulanxiolytics (Cryan J F, Holmes A. Nat Rev Drug Discov 2005, 4(9):775-90).

Example 14 Bladder Pressure- and Hypertrophy-Induced Models of UrinaryIncontinence

Compounds of Formula (I) can be tested in animal models of urinaryincontinence according to previously documented and validated methods,such as those described by in the scientific literature (Kaiser S, PlathT, (Metagen Pharmaceuticals GmbH, Germany). 2003 De patent 10215321;McMurray G, et al. Br J Pharmacol 2006, 147 Suppl 2: S62-79). TRPM8 isexpressed in human prostate, testicle, seminiferous tubules, scrotalskin and inflamed bladder (Stein R J, et al. J Urol. 2004, 172(3):1175-8); (Stein R J, et al. J Urol. 2004, 172(3): 1175-8; Mukerji et al.BMC Urology 2006, 6:6). Excitation of TRPM8 receptors through cooling orapplication of menthol causes contraction in the bladder and a decreasein micturation threshold volume (Tsukimi Y, Mizuyachi K, et al. Urology.2005, 65(2): 406-10). To assess compounds of Formula (I) for potentialurinary incontinence activity, Sprague-Dawley rats are surgicallyimplanted with bladder catheters allowing for the delivery of fluid(typically saline) and the monitoring of pressure (using a pressuretransducer). Cystometry recordings can be monitored with a polygraph toevaluate voiding interval, threshold pressure, bladder capacity, bladdercompliance, and the number of spontaneous bladder contractions. Forexample, the bladder catheter can be connected to a Harvard infusionpump, and bladders perfused overnight with saline at 2 mL/h. The nextmorning the bladder catheter can be attached (using a “T” connector) toa Statham pressure transducer (Model P23 Db) and to a Harvard infusionpump. A plastic beaker attached to a force displacement transducer(Grass FTO3) can be placed under the rat's cage to collect and recordurine volume. The cystometric evaluation of bladder function can bestarted by infusing saline (20 mL/h) and after the first micturition theinfusion is maintained for 20 min. Two hours after the first cystometryperiod, the rats can be dosed orally with a test compound of Formula (I)and a second cystometry is performed between 30 min and 4 h afteradministration of test compound. The appropriate vehicle (e.g. 10%Solutol in sterile water) can be similarly administered to groups ofrats that served as controls and the cystometry can be performed at thesame respective time points.

The compounds of the present invention can also be evaluated underconditions of bladder hypertrophy and instability. Under anesthesia, asilk ligature is tied around the proximal urethra of rodents producing apartial outlet obstruction and subsequent hypertrophied bladderdevelopment within 6-9 weeks (Woods M. et al., J. Urology. 2001,166:1142-47). Cystometry recordings can then be evaluated as describedabove. Such preclinical procedures are sensitive to compounds havingclinical utility for the treatment of urinary incontinence (Soulard C,et al. J Pharmacol Exp Ther 1992, 260(3): 1152-8).

Example 15 In Vivo Model for Cold-Enhanced Central Pain States

Injury to the brain or spinal cord, such as that caused by trauma,interrupted blood flow or neurodegenerative diseases, often precipitatesa central pain condition. Examples of such injuries characterized, inpart by, a hypersensitivity to cold stimuli include multiple sclerosis(Morin C, et al. Clin J Pain. 2002, 18(3): 191-5; Svendsen K B, et al.Pain. 2005, 114(3): 473-81), stroke or cerebral ischemia (Greenspan J D,et al. Pain. 2004, 109(3): 357-66) and spinal cord injury (Defrin R,Ohry A, Blumen N, Urca G. Pain 2001, 89(2-3): 253-63; Defrin R, et al.Brain 2002, 125(Pt 3): 501-10; Finnerup N B, et al. Anesthesiology 2005,102(5): 1023-30). Each of these conditions may be readily modeled inanimals for assessment of the ability of compounds of Formula (I) tomollify the hypersensitive state. For example, a spinal cord injury(SCI) can be performed in adult Sprague-Dawley rats having a body weightof 150-200 g at time of surgery (Erichsen et al. Pain 2005, 116:347-358). The rats can be anaesthetized with chloral hydrate (300 mg/kg,i.p., Sigma, USA) and a catheter can be inserted into the jugular vein.A midline skin incision can then be made along the back to expose theT11-L2 vertebrae. The animals can be positioned beneath a tunable argonion laser (Innova model 70, Coherent Laser Products Division, CA, USA)operating at a wavelength of 514 nm with an average power of 0.17 W. Thelaser light can be focused into a thin beam covering the single T13vertebra, which can be irradiated for 10 min. Immediately before theirradiation, erythrosin B (Aldrich, 32.5 mg/kg dissolved in 0.9% saline)can be injected intravenously via the jugular catheter. Due to rapidmetabolism of erythrosin B, the injection can be repeated after 5 min inorder to maintain adequate blood concentrations. During irradiation, thebody core temperature can be maintained at 37-38° C. by a heating pad.After irradiation the wound can be closed in layers and the skin suturedtogether.

SCI rats can be routinely tested for the presence of pain-like behaviorsfrom 3-4 weeks after surgery. The fur of the animals can be shaved atleast a day prior to examination of the cutaneous pain threshold toavoid sensitization of the skin receptors. During testing, the rats canbe gently held in a standing position by the experimenter and the flankarea and hindlimbs can be examined for hypersensitivity to sensorystimulation. On the day of drug testing, SCI rats can be administereddrug according to the experimental schedule and the time course ofpain-like behaviors can be measured. To test for the presence of coldallodynia, ethyl chloride or acetone can be sprayed onto the skin of theanimals, often that which has been previously determined to be sensitiveto mechanical stimulation by von Fry filament testing. The subsequentresponse to cold stimulation can be observed and classified according tothe following scale: 0, no visible response; 1, localized response (skintwitch) without vocalization; 2, transient vocalization; 3, sustainedvocalization. Kruskal Wallis ANOVA on ranks can be used to analyze theoverall effects of non-parametric data obtained in response to coldstimulation following pretreatment with either a compound of Formula (I)or vehicle.

Example 16 In Vivo Model for Post-Anesthetic Shivering

Spontaneous post-anesthetic tremor that resembles shivering is commonduring recovery from anesthesia. Risks to postoperative patients includean increase in metabolic rate of up to 400%, hypoxemia, wounddehiscence, dental damage, and disruption of delicate surgical repairs.The etiology of spontaneous post-anesthetic tremor is most commonlyattributed to normal thermoregulatory shivering in response tointraoperative hypothermia. In most operating and recovery rooms,shivering is controlled by the use of humidifiers, warming blankets, andinhalation of humidified heated oxygen. However, pharmacological controlis an effective alternate treatment modality (Bhatnagar S, et al.Anaesth Intensive Care 2001, 29(2): 149-54; Tsai Y C, Chu K S. AnesthAnalg 2001, 93(5): 1288-92). Compounds of Formula (I) may be assessedfor their ability to mitigate post-anesthetic induced-shaking by usinganimal models such as that described by Nikki et al (Nikki P, TammistoT. Acta Anaesthesiol Scand 1968, 12(3): 125-34 and Grahn (Grahn, D A, etal. J Applied Physiology. 1996, 81: 2547-2554). For example, Wistar rats(males, weighing 250-450 g) may be surgically implanted with an EEG/EMGrecording array to assess post anesthetic tremor activity. The EEGelectrodes are located bilaterally 2 mm off midline and adjacent tobregma and lamda. Following a one-week recovery period,frontal-occipital EEG, raw EMG, and integrated EMG activities, as wellas three temperatures (skin, rectal, and water blanket temperaturesduring anesthesia), and ambient temperature post-anesthesia can bemonitored throughout the experiment using copper-constantinthermocouples. The EEG and EMG signals can be recorded on polygraphpaper (5 mm/s, Grass model 7E polygraph) and, during recovery fromanesthesia, the EEG is computer scored in 10 second epochs as eithersynchronized: high amplitude (0.100 μV), low frequency (1-4 Hzdominated) activity characteristic of slow-wave sleep (SWS-like) ordesynchronized: low amplitude (0.75 μV), high frequency (5-15 Hzdominated), characteristic of waking and rapid-eye-movement sleep(W-like). The EMG activity can be quantified as the averaged summedvoltage/time interval by processing the raw EMG signal through anintegrator (Grass model 7P3, 0.5 s time constant). On the day of anexperiment, the animal can be placed in a small acrylic box (15×15×15cm) and exposed to a halothane vapor-air mixture (4% halothane).Immediately after the induction of anesthesia, the animal can be removedfrom the enclosure and subsequently anesthetized through a nose cone.Following cessation of anesthesia, two stages of recovery can be judged:emergence from anesthesia and restoration of behavioral activity(behavioral recovery). Emergence from anesthesia may be defined as anincrease in tonic EMG activity and a change in the EEG from a SWS-likepattern to a W-like pattern. Behaviorally, recovery has occurred whenthe animal rises from a prone position and initiated coordinatedmovements. The time intervals from termination of anesthesia toemergence and behavioral recovery can be measured in all animals. Timeinterval data can be subjected to a repeated measure analysis ofvariance, and the Scheffe's method can be employed for testingdifferences between pairs of means.

Example 17 TRPM8 Patch Clamp Assays

For patch clamp experiments, HEK293 cells stably transfected with canineTRPM8 were cultured in DMEM supplemented with 10% fetal bovine serum,100 units/ml penicillin, 100 μg/ml streptomycin and 1 mg/ml G418. Cellswere maintained at 37° C. and in 5% CO₂.

The extracellular solution contained (in mM): NaCl, 132; EGTA, 1; KCl,5.4; MgCl₂, 0.8; HEPES, 10; glucose, 10; pH=7.4. Recordings wereperformed using the conventional whole-cell patch clamp technique, 1-2days after plating cells onto glass coverslips at densities appropriatefor single cell recording. Currents were amplified by a patch clampamplifier and filtered at 2 kHz (Axopatch 200B, Molecular Devices, UnionCity, Calif.). Menthol (100 μM) was applied to the cell at 0.5 ml/minvia a gravity-fed perfusion system. Recordings involving mentholactivation were performed at 22° C.

In experiments where temperatures were varied, temperature ramps weregenerated by cooling the perfusate in an in-line cooler (Model SC-20,Warner Instruments, Hamden, Conn.) controlled by a temperaturecontroller (Model CL-100, Warner Instruments). The temperature in thevicinity of the recorded cell was measured with a custom-made miniaturethermo-microprobe connected to a monitoring thermometer (Model TH-8,Physitemp, Clifton, N.J.), and sampled using Digidata 1322A and pClamp9.0 (Molecular Devices), as were the currents concurrently measured inthe whole-cell patch clamp mode. The current was continuously sampled(at 100 Hz) at a holding potential of −60 mV.

Compounds were diluted from 10 mM DMSO stocks (stored at −20° C.) intoan extracellular solution either containing 100 μM menthol or subjectingto cooling. Increasing concentrations of a compound were applied to acell in a cumulative manner and concentration-dependent responses weremeasured after steady-state activation was achieved by either 100 μMmenthol or cooling to 10° C. A saturating concentration of a referenceantagonist was applied at the end of an experiment (either in thepresence of 100 μM menthol or 10° C. temperature) to establish thebaseline from which all the other measurements were subtracted.

Percentage inhibition by a compound was calculated as follows:100×(1−I_(comp)/I₀); where I_(comp) and I₀ are steady-state currentamplitudes in either the presence or absence of a concentration of thecompound. Concentration-response data were fitted to a logistic functionas follows: R=100/(1+c/IC₅₀)^(p); where, R is the percentage inhibition,p is the Hill coefficient and c is the concentration of the testcompound. The resultant data are displayed in Table 11.

TABLE 11 Mode of Activation Menthol Cold (100 μM) (10° C.) Cpd IC₅₀ (μM)IC₅₀ (μM) 155 0.0125 234 0.0047 0.0016 235 0.0592 236 0.0014 0.0029 2380.00053 239 0.0030 0.0058 241 0.0016 242 0.0004

Example 18 In Vitro Rat and Human TRPM8 Functional Assay

For functional expression of TRPM8, the full-length cDNAs encoding humanand rat TRPM8 were subcloned into pCI-NEO mammalian expression vectors.The expression constructs were transiently transfected into HEK293 cellsaccording to the FuGENE 6 Transfection Reagent® (ROCHE) instructions.HEK293 cells were routinely grown as monolayers in Dulbecco's minimumessential medium supplemented with 10% FBS, 1 mM L-glutamine, 100units/mL penicillin and 100 ug/mL streptomycin. Cells were maintained in5% CO₂ at 37° C. Within twenty-four hours, transiently transfected humanand rat TRPM8 were seeded into clear-base poly-D-lysine coated 384-wellplates (BD Biosciences, NJ, USA) at a density of 10,000 cells per wellin culture medium and grown overnight. The following day, all medium wasremoved and the cells were incubated with 52 μL of 0.5× calcium 3 dye(Molecular Devices) prepared in complete assay buffer containing 20 mMHEPES, 0.1% BSA, and 2.5 mM probenecid at 37° C. for thirty fiveminutes. The cells were then incubated for an additional fifteen minutesat room temperature before initiating experiments. Following incubation,plates were inserted into a FDSS instrument, where cells were challengedwith a compound of Formula (I) (at varying concentrations) andintracellular Ca²⁺ was measured for 5 min prior to the addition of 100nM icilin. IC₅₀ values for compounds of the present invention weredetermined from eight-point dose-response studies

Maximal fluorescence intensity (FI) achieved upon addition of icilin wasexported from the FDSS and further analyzed using GraphPad Prism 3.02(Graph Pad Software Inc., CA, U.S.A.). Basal FI was subtracted prior tonormalizing data to percent of maximal response. The dose responsecurves from the average of quadruplicate wells for each data point wereanalyzed by using nonlinear regression of either sigmoidal dose responseor sigmoidal dose response (variable slope). Finally, the IC₅₀ valueswere calculated with the best-fit dose curve determined by Prism. Theresultant data are displayed in Table 12.

TABLE 12 Receptor Subtype rTRPM8 hTRPM8 Cpd IC₅₀ (nm) IC₅₀ (nm) 2340.053 0.054 236 0.140 0.126 239 0.052 0.044 242 0.056 0.049

Example 19 Cold Pressor Test

Compounds of Formula (I) can be tested in animals and humans for theirability to mitigate cardiovascular pressor responses evoked by coldexposure. The clinical cold pressor test assesses changes in bloodpressure (BP) and cold pain perception during a 2-3 minute immersion ofone hand into ice water. This test may be utilized to characterizeanalgesic compounds (Koltzenberg M et al. Pain. 2006, 126(1-3): 165-74)and to assess cold hypersensitivity (Desmeules J A et al. ArthritisRheum. 2003, 48(5): 1420-9). A compound of Formula (I) was studied in ananesthetized rat cold pressor paradigm to determine whether TRPM8antagonism would interfere with the blood pressure pressor response tocold stimulation of the forepaws. Male Sprague-Dawley rats (300-450 g)anesthetized with sodium pentobarbital were instrumented with a jugularcatheter and an indwelling carotid artery pressure transducer. Vehicle(10% Solutol in water) or test compound was infused (1 mL/kg) over oneminute through the intravenous catheter. Ten minutes later bothforelimbs were packed in crushed ice for 5 minutes. Percent changes inmean arterial pressure in response to this cold stimulus were calculatedfor vehicle and test compound pretreatments. Percent inhibitionattributed to treatment with test compound was then determined using thefollowing formula: % Inhibition=[1−(cold evoked % change in BP post-testcompound/cold evoked % change in BP post-vehicle)]×100. The resultantdata are displayed in Table 13.

TABLE 13 Inhibition of Cold-induced Pressor Response in AnesthetizedRat. Dose Cpd (mg/kg) Route % I Time 242 6 i.v. 54 10′

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of Formula (I):

wherein: A is benzo or pyrido; wherein benzo is optionally substitutedwith a substituent selected from the group consisting of C₁₋₂alkyl,C₁₋₂alkoxy, hydroxy, fluoro, chloro, bromo, C₁₋₂alkoxycarbonyl,aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, di(C₁₋₂alkyl)aminocarbonyl, andtrifluoromethyl; and benzo is optionally further substituted with asubstituent selected from the group consisting of methyl, methoxy,hydroxy, fluoro, and chloro; and wherein pyrido is optionallysubstituted with a substituent selected from the group consisting offluoro, chloro, bromo, and methyl; and pyrido is optionally furthersubstituted with fluoro; D is d-2

X is O, S, S(═O), S(O₂), or N—R₆; wherein R₆ is phenyl, C₁₋₄-alkyl,allyl, C₁₋₄-alkylsulfonyl, C₁₋₄alkylcarbonyl, or pyridinyl; W is C(R₄)or N; R₄ is hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy; C₁₋₆alkoxycarbonyl; chloro;bromo; cyano; trifluoromethyl; phenyl; a heteroaryl selected from thegroup consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,pyrazolyl, pyridinyl, and pyrimidinyl; or a C₃₋₆cycloalkyl; whereinphenyl is optionally substituted with an aminocarbonyl, trifluoromethyl,or trifluoromethoxy substituent; or phenyl is optionally substitutedwith one to two substituents independently selected from the groupconsisting of C₁₋₂alkyl, C₁₋₂alkoxy, fluoro, chloro, hydroxy, and cyano;and wherein heteroaryl is optionally substituted with bromo or one totwo substituents independently selected from the group consisting ofmethyl, fluoro, and chloro; R₁ and R₂ are independently selected fromthe group consisting of C₁₋₈alkyl; C₁₋₈alkoxy; —O(CH₂)_(p)O(CH₂)—CH₃;—O(CH₂)_(p)O(CH₂)_(q)OCH₃; —O(CH₂)_(r)C(O)OCH₃; —O(CH₂)_(p)OC(O)CH₃;—(CH₂)_(p)O(CH₂)—CH₃; phenyl(C₁₋₃)alkyl; phenyl(C₁₋₃)alkoxy; andC₃₋₈cycloalkyloxy; wherein p is an integer from 2 to 6; and wherein q isan integer from 0 to 4, such that the sum of p and q is less than orequal to six; wherein r is an integer from 1 to 4; and, wherein thephenyl portion of phenyl(C₁₋₃)alkyl and phenyl(C₁₋₃)alkoxy is optionallysubstituted with one to two substituents independently selected from thegroup consisting of C₁₋₂alkyl, C₁₋₂alkoxy, trifluoromethyl, hydroxy,cyano, and halogen; and further, wherein C₁₋₈alkyl and C₁₋₈alkoxy of R₁and R₂ are optionally substituted with hydroxy, difluoromethyl,trifluoromethyl, C₃₋₆cycloalkyl, carboxy, C₁₋₂alkoxycarbonyl,di(C₁₋₃alkyl)amino, aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, ordi(C₁₋₃alkyl)aminocarbonyl; provided that when R₁ is2-(N,N-dimethylamino)-ethoxy, R₂ is other than2-(N,N-dimethylamino)-ethoxy; R₃ is hydrogen, methyl, fluoro, chloro,bromo, or hydroxy; or R₃ is absent when L is alkene ═CH—; L is—(CH₂)_(n)—, —OC₁₋₂alkyl-, or ═CH—; wherein n is 1 or 2; B is hydrogen,phenyl, naphthyl, or a heteroaryl selected from the group consisting ofbenzothiophenyl, benzo(1,3)dioxalyl, oxazolyl, thienyl, furanyl, andbenzofuranyl; wherein the phenyl of B is optionally substituted withhydroxy, C₁₋₃alkoxy, trifluoromethyl, nitro, amino, phenyl or aheteroaryl selected from the group consisting of pyridinyl, thienyl,furanyl, pyrrolyl, oxazolyl, and thiazolyl; and wherein phenyl of B isoptionally further substituted with a substituent selected from thegroup consisting of methyl, fluoro, chloro, trifluoromethyl, methoxy,and hydroxy; and wherein the naphthyl of B is optionally substitutedwith 1 or 2 substituents selected from the group consisting of hydrogen,methyl, fluoro, chloro, bromo, C₁₋₃alkoxy, hydroxyl, and dimethylamino;or, the phenyl or heteroaryl substituent of B is optionally substitutedwith a substituent independently selected from the group consisting ofC₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylthio, fluoro, chloro, bromo, cyano,hydroxy, trifluoromethyl, trifluoromethylthio, trifluoromethoxy,difluoromethoxy, trifluoromethanesulfonyl, C₁₋₂alkoxycarbonyl,aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, and di(C₁₋₂alkyl)aminocarbonyl;and the phenyl or heteroaryl substituent of B is optionally furthersubstituted with one to two fluoro or chloro substituents; provided thatwhen B is hydrogen and L is absent or —(CH₂)_(n)—, then at least one ofR₁ and R₂ is selected from the group consisting of phenyl(C₁₋₆)alkyl andphenyl(C₁₋₆)alkoxy; and enantiomers, diastereomers, racemates, andpharmaceutically acceptable salts thereof; provided that a compound ofFormula (I) is other than a compound wherein A is 5-fluoro-benzo, D isd-2, W is C(R₄), R₄ is methyl, X is S, R₁ and R₂ are each isopropyloxy,R₃ is hydrogen, L is CH₂, and B is 3,4-difluorophenyl; a compoundwherein A is 6-trifluoromethyl-benzo, D is d-2, W is C (R₄), R₄ ismethyl, X is S, R₁ and R₂ are each ethoxy, R₃ is hydrogen, L is CH₂, andB is 3,4-difluorophenyl; and further provided that when D is d-2, R₃ ishydrogen, and L is —(CH₂)_(n)—, then B is optionally substituted with asubstituent other than aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, ordi(C₁₋₂alkyl)aminocarbonyl.
 2. The compound of claim 1 wherein when W isN, X is other than N—R₆.
 3. The compound of claim 1 wherein A isunsubstituted pyrido or benzo optionally substituted withtrifluoromethyl, C₁₋₂alkyl, fluoro, chloro, bromo, or C₁₋₂alkoxy, andoptionally further substituted with a substituent selected from thegroup consisting of methyl, methoxy, fluoro, and chloro.
 4. The compoundof claim 3 wherein A is benzo optionally substituted withtrifluoromethyl, C₁₋₂alkyl, C₁₋₂alkoxy, fluoro, chloro, or bromo.
 5. Thecompound of claim 4 wherein A is benzo optionally substituted withC₁₋₂alkyl, fluoro, or chloro.
 6. The compound of claim 1 wherein X is O,S, S(O₂), or N—R₆; wherein R₆ is phenyl; provided that when W is N, X isother than N—R₆.
 7. The compound of claim 6 wherein X is O, S, or S(O₂).8. The compound of claim 7 wherein X is O or S.
 9. The compound of claim1 wherein W is C(R₄).
 10. The compound of claim 1 wherein R₄ ishydrogen; C₁₋₆alkyl; chloro; bromo; trifluoromethyl; phenyl optionallysubstituted with hydroxy, aminocarbonyl, or fluoro; pyridinyl optionallysubstituted with fluoro; thienyl; or C₃₋₆cycloalkyl.
 11. The compound ofclaim 10 wherein C₁₋₆alkyl is methyl, isopropyl, or 2,2-dimethyl-propyl.12. The compound of claim 11 wherein R₄ is hydrogen; methyl; isopropyl;2,2-dimethyl-propyl; chloro; bromo; trifluoromethyl; phenyl optionallysubstituted with hydroxy or fluoro; pyridinyl optionally substitutedwith fluoro; thienyl; or C₃₋₆cycloalkyl.
 13. The compound of claim 12wherein C₃₋₆cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.
 14. The compound of claim 13 wherein R₄ is methyl;isopropyl; chloro; bromo; trifluoromethyl; pyridinyl optionallysubstituted with fluoro; thienyl; cyclopropyl; cyclobutyl; orcyclopentyl.
 15. The compound of claim 1 wherein R₁ and R₂ areindependently selected from the group consisting of C₁₋₄-alkyloptionally substituted with di(C₁₋₃alkyl)amino; C₁₋₅alkoxy optionallysubstituted with di(C₁₋₃alkyl)amino; —O(CH₂)_(p)O(CH₂)_(q)CH₃;—O(CH₂)_(r)C(O)OCH₃; —O(CH₂)_(p)OC(O)CH₃; phenyl(C₁₋₃)alkyl;phenyl(C₁₋₃)alkoxy; and C₃₋₆cycloalkyloxy; wherein p is an integer from2 to 4, q is 0, and r is 1; wherein the phenyl portion ofphenyl(C₁₋₃)alkyl and phenyl(C₁₋₃)alkoxy is optionally substituted withone to two substituents independently selected from the group consistingof methyl, methoxy, fluoro, chloro, and bromo; provided that when R₁ is2-(N,N-dimethylamino)-ethoxy, R₂ is other than2-(N,N-dimethylamino)-ethoxy; further provided that only one of R₁ andR₂ is phenyl(C₁₋₃)alkyl or phenyl(C₁₋₃)alkoxy.
 16. The compound of claim15 wherein R₁ and R₂ are independently selected from the groupconsisting of C₁₋₄-alkyl, phenyl(C₁₋₃)alkyl, —OCH₂C(O)OCH₃,—O(CH₂)₂OC(O)CH₃, and C₁₋₄-alkoxy; wherein the phenyl portion ofphenyl(C₁₋₃)alkyl is optionally substituted with methoxy.
 17. Thecompound of claim 16 wherein C₁₋₄alkyl is methyl or isobutyl.
 18. Thecompound of claim 17 wherein C₁₋₄-alkoxy is ethoxy or isopropyloxy. 19.The compound of claim 1 wherein R₃ is hydrogen, methyl, fluoro, orbromo; or R₃ is absent when L is ═CH—.
 20. The compound of claim 19wherein R₃ is hydrogen or methyl; or R₃ is absent when L is ═CH—. 21.The compound of claim 20 wherein R₃ is hydrogen or methyl.
 22. Thecompound of claim 21 wherein R₃ is hydrogen.
 23. The compound of claim 1wherein L is —(CH₂)_(n)—, —OCH₂—, or ═CH—; and n is 1 or
 2. 24. Thecompound of claim 23 wherein L is —(CH₂)_(n)—, —OCH₂—, or ═CH—; and nis
 1. 25. The compound of claim 24 wherein L is —(CH₂)_(n)—; and n is 1.26. The compound of claim 1 wherein B is phenyl, naphthyl, or aheteroaryl selected from the group consisting of benzothiophenyl andbenzo(1,3)dioxalyl; wherein the phenyl of B is optionally substitutedwith phenyl or pyridinyl; and the phenyl of B is optionally furthersubstituted with a substituent independently selected from the groupconsisting of methyl, fluoro, and chloro; or, the phenyl or heteroarylof B is optionally substituted with a substituent selected from thegroup consisting of C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro, bromo, cyano,hydroxy, trifluoromethyl, trifluoromethoxy, C₁₋₂alkoxycarbonyl,aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, and di(C₁₋₂alkyl)aminocarbonyl;and B is optionally further substituted with a chloro or fluorosubstituent; provided that when R₃ is hydrogen, and L is —(CH₂)_(n)—wherein n is 1 or 2, B is optionally substituted with a substituentother than aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, ordi(C₁₋₃alkyl)aminocarbonyl.
 27. The compound of claim 26 wherein B isphenyl, naphthyl, or benzo(1,3)dioxalyl; wherein the phenyl of B isoptionally substituted with phenyl or pyridinyl; or, B other thannaphthyl is optionally substituted with a substituent selected from thegroup consisting of C₁₋₃alkyl, fluoro, chloro, bromo, trifluoromethyl,and trifluoromethoxy; and B is optionally further substituted with achloro or fluoro substituent.
 28. The compound of claim 27 wherein B isphenyl optionally substituted with phenyl or pyridinyl; or, B is phenyloptionally substituted with a substituent independently selected fromthe group consisting of C₁₋₃alkyl, fluoro, chloro, bromo,trifluoromethyl, and trifluoromethoxy; and B is optionally furthersubstituted with a chloro or fluoro substituent.
 29. The compound ofclaim 28 wherein B is phenyl substituted with a substituent selectedfrom the group consisting of C₁₋₃alkyl, fluoro, chloro, bromo,trifluoromethyl, and trifluoromethoxy; and B is optionally furthersubstituted with a chloro or fluoro substituent.
 30. The compound ofclaim 29 wherein B is phenyl substituted with a substituent selectedfrom the group consisting of fluoro, chloro, and trifluoromethyl; and Bis optionally further substituted with a chloro or fluoro substituent.31. A compound of Formula (I)

wherein A is unsubstituted pyrido or benzo optionally substituted withtrifluoromethyl, C₁₋₂alkyl, fluoro, chloro, bromo, or C₁₋₂alkoxy, andoptionally further substituted with a substituent selected from thegroup consisting of methyl, methoxy, fluoro, and chloro; D is d-2

X is O, S, S(O₂), or N—R₆; wherein R₆ is phenyl; provided that when W isN, then X is other than N—R₆; W is C(R₄) or N; provided that when W isN, X is other than N—R₆; R₄ is hydrogen; C₁₋₆alkyl; chloro; bromo;trifluoromethyl; phenyl optionally substituted with hydroxy,aminocarbonyl, or fluoro; pyridinyl optionally substituted with fluoro;thienyl; or C₃₋₆cycloalkyl; R₁ and R₂ are independently selected fromthe group consisting of C₁₋₄alkyl optionally substituted withdi(C₁₋₃alkyl)amino; C₁₋₅alkoxy optionally substituted withdi(C₁₋₃alkyl)amino; —O(CH₂)_(p)O(CH₂)—CH₃; —O(CH₂)_(r)C(O)OCH₃;—O(CH₂)_(p)OC(O)CH₃; phenyl(C₁₋₃)alkyl; phenyl(C₁₋₃)alkoxy; andC₃₋₆cycloalkyloxy; wherein p is an integer from 2 to 4, q is 0, and r is1; wherein the phenyl portion of phenyl(C₁₋₃)alkyl andphenyl(C₁₋₃)alkoxy is optionally substituted with one to twosubstituents independently selected from the group consisting of methyl,methoxy, fluoro, chloro, and bromo; provided that when R₁ is2-(N,N-dimethylamino)-ethoxy, R₂ is other than2-(N,N-dimethylamino)-ethoxy; further provided that only one of R₁ andR₂ is phenyl(C₁₋₃)alkyl or phenyl(C₁₋₃)alkoxy; R₃ is hydrogen, methyl,fluoro, or bromo; or R₃ is absent when L is ═CH—; L is —(CH₂)—, —OCH₂—,or ═CH—; and n is 1 or 2; B is phenyl, naphthyl, or a heteroarylselected from the group consisting of benzothiophenyl andbenzo(1,3)dioxalyl; wherein the phenyl of B is optionally substitutedwith phenyl or pyridinyl; and the phenyl of B is optionally furthersubstituted with a substituent independently selected from the groupconsisting of methyl, fluoro, and chloro; or, the phenyl or heteroarylof B is optionally substituted with a substituent selected from thegroup consisting of C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro, bromo, cyano,hydroxy, trifluoromethyl, trifluoromethoxy, C₁₋₂alkoxycarbonyl,aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, and di(C₁₋₂alkyl)aminocarbonyl;and B is optionally further substituted with a chloro or fluorosubstituent; provided that when R₃ is hydrogen, and L is —(CH₂)_(n)—wherein n is 1 or 2, B is optionally substituted with a substituentother than aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, ordi(C₁₋₃alkyl)aminocarbonyl; provided that a compound of Formula (I) isother than a compound wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄),R₄ is methyl, X is S, R₁ and R₂ are each isopropyloxy, R₃ is hydrogen, Lis CH₂, and B is 3,4-difluorophenyl; or a compound wherein A is6-trifluoromethyl-benzo, D is d-2, W is C(R₄), R₄ is methyl, X is S, R₁and R₂ are each ethoxy, R₃ is hydrogen, L is CH₂, and B is3,4-difluorophenyl; and further provided that when D is d-2, R₃ ishydrogen, and L is —(CH₂)_(n)—, then B is optionally substituted with asubstituent other than aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, ordi(C₁₋₃alkyl)aminocarbonyl.
 32. The compound of claim 31 wherein: A isunsubstituted pyrido or benzo optionally substituted withtrifluoromethyl, C₁₋₂alkyl, fluoro, chloro, bromo, or C₁₋₂alkoxy, andoptionally further substituted with a substituent selected from thegroup consisting of methyl, methoxy, fluoro, and chloro; X is O, S,S(O₂), or N—R₆; wherein R₆ is phenyl; provided that when W is N, X isother than N—R₆; W is C(R₄) or N; R₄ is hydrogen; C₁₋₆alkyl; chloro;bromo; trifluoromethyl; phenyl optionally substituted with hydroxy,aminocarbonyl, or fluoro; pyridinyl optionally substituted with fluoro;thienyl; or C₃₋₆cycloalkyl; R₁ and R₂ are independently selected fromthe group consisting of C₁₋₄alkyl optionally substituted withdi(C₁₋₃alkyl)amino; C₁₋₅alkoxy optionally substituted withdi(C₁₋₃alkyl)amino; —O(CH₂)_(p)O(CH₂)—CH₃; —O(CH₂)_(r)C(O)OCH₃;—O(CH₂)_(p)OC(O)CH₃; phenyl(C₁₋₃)alkyl; phenyl(C₁₋₃)alkoxy; andC₃₋₆cycloalkyloxy; wherein p is an integer from 2 to 4, q is 0, and r is1; wherein the phenyl portion of phenyl(C₁₋₃)alkyl andphenyl(C₁₋₃)alkoxy is optionally substituted with one to twosubstituents independently selected from the group consisting of methyl,methoxy, fluoro, chloro, and bromo; provided that when R₁ is2-(N,N-dimethylamino)-ethoxy, R₂ is other than2-(N,N-dimethylamino)-ethoxy; further provided that only one of R₁ andR₂ is phenyl(C₁₋₃)alkyl or phenyl(C₁₋₃)alkoxy; R₃ is hydrogen, methyl,fluoro, or bromo; L is —(CH₂)—, or —OCH₂—; and n is 1 or 2; B is phenyl,naphthyl, or a heteroaryl selected from the group consisting ofbenzothiophenyl and benzo(1,3)dioxalyl; wherein the phenyl of B isoptionally substituted with phenyl or pyridinyl; and the phenyl of B isoptionally further substituted with a substituent independently selectedfrom the group consisting of methyl, fluoro, and chloro; or, the phenylor heteroaryl of B is optionally substituted with a substituent selectedfrom the group consisting of C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro,bromo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy,C₁₋₂alkoxycarbonyl, aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, anddi(C₁₋₂alkyl)aminocarbonyl; and B is optionally further substituted witha chloro or fluoro substituent; provided that when R₃ is hydrogen, and Lis —(CH₂)_(n)— wherein n is 1 or 2, B is optionally substituted with asubstituent other than aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, ordi(C₁₋₃alkyl)aminocarbonyl; provided that a compound of Formula (I) isother than a compound wherein A is 5-fluoro-benzo, D is d-2, W is C(R₄),R₄ is methyl, X is S, R₁ and R₂ are each isopropyloxy, R₃ is hydrogen, Lis CH₂, and B is 3,4-difluorophenyl; or a compound wherein A is6-trifluoromethyl-benzo, D is d-2, W is C(R₄), R₄ is methyl, X is S, R₁and R₂ are each ethoxy, R₃ is hydrogen, L is CH₂, and B is3,4-difluorophenyl; and further provided that when D is d-2, R₃ ishydrogen, and L is —(CH₂)_(n)—, then B is optionally substituted with asubstituent other than aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, ordi(C₁₋₃alkyl)aminocarbonyl.
 33. The compound of claim 32 wherein A isbenzo optionally substituted with trifluoromethyl, C₁₋₂alkyl,C₁₋₂alkoxy, fluoro, chloro, or bromo; X is O, S, or S(O₂); W is C(R₄);R₄ is hydrogen; methyl; isopropyl; 2,2-dimethyl-propyl; chloro; bromo;trifluoromethyl; phenyl optionally substituted with hydroxy,aminocarbonyl, or fluoro; pyridinyl optionally substituted with fluoro;thienyl; or C₃₋₆cycloalkyl; R₁ and R₂ are independently selected fromthe group consisting of C₁₋₄alkyl, phenyl(C₁₋₃)alkyl, —OCH₂C(O)OCH₃,—O(CH₂)₂OC(O)CH₃, and C₁₋₄alkoxy; wherein the phenyl portion ofphenyl(C₁₋₃)alkyl is optionally substituted with methoxy; R₃ is hydrogenor methyl; or R₃ is absent when L is ═CH—; L is —(CH₂)_(n)—, —OCH₂—, or═CH—; and n is 1; B is phenyl, naphthyl, or benzo(1,3)dioxalyl; whereinthe phenyl of B is optionally substituted with phenyl or pyridinyl; or,B other than naphthyl is optionally substituted with a substituentselected from the group consisting of C₁₋₃alkyl, fluoro, chloro, bromo,trifluoromethyl, and trifluoromethoxy; and B is optionally furthersubstituted with a chloro or fluoro substituent; and enantiomers,diastereomers, racemates, and pharmaceutically acceptable salts thereof;provided that a compound of Formula (I) is other than a compound whereinA is 5-fluoro-benzo, D is d-2, W is C(R₄), R₄ is methyl, X is S, R₁ andR₂ are each isopropyloxy, R₃ is hydrogen, L is CH₂, and B is3,4-difluorophenyl; or a compound wherein A is 6-trifluoromethyl-benzo,D is d-2, W is C(R₄), R₄ is methyl, X is S, R₁ and R₂ are each ethoxy,R₃ is hydrogen, L is CH₂, and B is 3,4-difluorophenyl; and furtherprovided that when D is d-2, R₃ is hydrogen, and L is —(CH₂)_(n)—, thenB is optionally substituted with a substituent other than aminocarbonyl,(C₁₋₃alkyl)aminocarbonyl, or di(C₁₋₃alkyl)aminocarbonyl.
 34. Thecompound of claim 33 wherein: A is benzo optionally substituted withC₁₋₂alkyl, fluoro, or chloro; X is O or S; W is C(R₄); R₄ is methyl;isopropyl; chloro; bromo; trifluoromethyl; phenyl optionally substitutedwith hydroxy or fluoro; pyridinyl optionally substituted with fluoro;thienyl; cyclopropyl; cyclobutyl; or cyclopentyl; R₁ and R₂ areindependently selected from the group consisting of methyl, isobutyl,ethoxy, and isopropyloxy; R₃ is hydrogen; L is —(CH₂)—; and n is 1; B isphenyl substituted with a substituent selected from the group consistingof C₁₋₃alkyl, fluoro, chloro, bromo, trifluoromethyl, andtrifluoromethoxy; and B is optionally further substituted with a chloroor fluoro substituent; and enantiomers, diastereomers, racemates, andpharmaceutically acceptable salts thereof; provided that a compound ofFormula (I) is other than a compound wherein A is 5-fluoro-benzo, D isd-2, W is C(R₄), R₄ is methyl, X is S, R₁ and R₂ are each isopropyloxy,R₃ is hydrogen, L is CH₂, and B is 3,4-difluorophenyl.
 35. The compoundof claim 34 wherein R₄ is methyl; isopropyl; chloro; bromo;trifluoromethyl; pyridinyl optionally substituted with fluoro;cyclopropyl; cyclobutyl; or cyclopentyl; and B is phenyl substitutedwith a substituent selected from the group consisting of C₁₋₃alkyl,fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; and B isoptionally further substituted with a chloro or fluoro substituent. 36.The compound of claim 35 wherein B is phenyl substituted with asubstituent selected from the group consisting of fluoro, chloro, andtrifluoromethyl; and B is optionally further substituted with a chloroor fluoro substituent.
 37. A pharmaceutical composition comprising acompound, salt or solvate according to claim 1 admixed with apharmaceutically acceptable carrier, excipient or diluent.
 38. Aveterinary composition comprising a compound, salt or solvate accordingto claim 1 admixed with a veterinarily acceptable carrier, excipient ordiluent.
 39. A compound of Formula (I)

wherein: A is benzo or pyrido; wherein benzo is optionally substitutedwith a substituent selected from the group consisting of hydrogen,C₁₋₂alkyl, C₁₋₂alkoxy, hydroxy, fluoro, chloro, bromo,C₁₋₂alkoxycarbonyl, aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl,di(C₁₋₂alkyl)aminocarbonyl, and trifluoromethyl; and benzo is optionallyfurther substituted with a substituent selected from the groupconsisting of hydrogen, methyl, methoxy, hydroxy, fluoro, chloro; andwherein pyrido is optionally substituted with a substituent selectedfrom the group consisting of fluoro, chloro, bromo, and methyl; andpyrido is optionally further substituted with fluoro; D is d-2

X is O, S, S(═O), S(O₂), or N—R₆; wherein R₆ is phenyl, C₁₋₄alkyl,allyl, C₁₋₄alkylsulfonyl, C₁₋₄alkylcarbonyl, or pyridinyl; W is C(R₄) orN; R₄ is hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy; C₁₋₆alkoxycarbonyl; chloro;bromo; cyano; trifluoromethyl; phenyl; a heteroaryl selected from thegroup consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,pyrazolyl, pyridinyl, and pyrimidinyl; or a C₃₋₆cycloalkyl; whereinphenyl is optionally substituted with a trifluoromethyl ortrifluoromethoxy substituent, or phenyl is optionally substituted withone to two substituents independently selected from the group consistingof hydrogen, C₁₋₂alkyl, C₁₋₂alkoxy, fluoro, chloro, hydroxy, and cyano;and wherein heteroaryl is optionally substituted with bromo or one totwo substituents independently selected from the group consisting ofmethyl, fluoro, and chloro; R₁ and R₂ are independently selected fromthe group consisting of C₁₋₈alkyl; C₁₋₈alkoxy; —O(CH₂)_(p)O(CH₂)_(q)CH₃;—(CH₂)_(p)O(CH₂)_(q)CH₃; phenyl(C₁₋₃)alkyl; phenyl(C₁₋₃)alkoxy; andC₃₋₈cycloalkyloxy; wherein p is an integer from 2 to 6; and wherein q isan integer from 0 to 4, such that the sum of p and q is less than orequal to six; and, wherein the phenyl portion of phenyl(C₁₋₃)alkyl andphenyl(C₁₋₃)alkoxy is optionally substituted with one to twosubstituents independently selected from the group consisting ofC₁₋₂alkyl, C₁₋₂alkoxy, trifluoromethyl, hydroxy, cyano, and halogen; andfurther, wherein C₁₋₈alkyl and C₁₋₈alkoxy of R₁ and R₂ are optionallysubstituted with hydroxy, difluoromethyl, trifluoromethyl,C₃₋₆cycloalkyl, carboxy, C₁₋₂alkoxycarbonyl, di(C₁₋₃alkyl)amino,aminocarbonyl, (C₁₋₃alkyl)aminocarbonyl, and di(C₁₋₃alkyl)aminocarbonyl;provided that when R₁ is 2-(N,N-dimethylamino)-ethoxy, R₂ is other than2-(N,N-dimethylamino)-ethoxy; R₃ is hydrogen, methyl, fluoro, chloro,bromo, or hydroxy; L is —(CH₂)_(n)—, or —OC₁₋₂alkyl-; wherein n is 1 or2; B is hydrogen, phenyl, naphthyl, or a heteroaryl selected from thegroup consisting of benzothiophenyl, benzo(1,3)dioxalyl, oxazolyl,thienyl, furanyl, and benzofuranyl; wherein the phenyl of B isoptionally substituted with phenyl or a heteroaryl selected from thegroup consisting of pyridinyl, thienyl, furanyl, oxazolyl, andthiazolyl; and wherein phenyl is optionally further substituted with asubstituent selected from the group consisting of methyl, fluoro,chloro, trifluoromethyl, methoxy, and hydroxy; and wherein the naphthylof B is optionally substituted with 1 or 2 substituents selected fromthe group consisting of hydrogen, methyl, fluoro, chloro, bromo,methoxy, hydroxyl, and dimethylamino; or, a B substituent other thanhydrogen is optionally substituted with a substituent independentlyselected from the group consisting of C₁₋₃alkyl, C₁₋₃alkoxy, fluoro,chloro, bromo, cyano, hydroxy, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, methanesulfonyl, trifluoromethanesulfonyl,C₁₋₂alkoxycarbonyl, aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, anddi(C₁₋₂alkyl)aminocarbonyl; and B is optionally further substituted withone to two fluoro or chloro substituents; provided that when B ishydrogen and L is absent or —(CH₂)_(n)—, then at least one of R₁ and R₂is selected from the group consisting of phenyl(C₁₋₆)alkyl andphenyl(C₁₋₆)alkoxy; and enantiomers, diastereomers, racemates, andpharmaceutically acceptable salts thereof; provided that a compound ofFormula (I) is other than a compound wherein A is 5-fluoro-benzo, D isd-2, W is C(R₄), R₄ is methyl, X is S, R₁ and R₂ are each isopropyloxy,R₃ is hydrogen, L is CH₂, and B is 3,4-difluorophenyl; or a compoundwherein A is 6-trifluoromethyl-benzo, D is d-2, W is C(R₄), R₄ ismethyl, X is S, R₁ and R₂ are each ethoxy, R₃ is hydrogen, L is CH₂, andB is 3,4-difluorophenyl; and further provided that when D is d-2, R₃ ishydrogen, and L is —(CH₂)_(n)—, then B is optionally substituted with asubstituent other than aminocarbonyl, (C₁₋₂alkyl)aminocarbonyl, ordi(C₁₋₂alkyl)aminocarbonyl.